Nrf2 REGULATORS

ABSTRACT

The present invention relates to aryl analogs, pharmaceutical compositions containing them and their use as NRF2 regulators.

FIELD OF THE INVENTION

The present invention relates to aryl analogs, pharmaceuticalcompositions containing them and their use as NRF2 regulators.

BACKGROUND OF THE INVENTION

NRF2 (NF-E2 related factor 2) is a member of the cap-n-collar (CNC)family of transcription factors containing a characteristicbasic-leucine zipper motif. Under basal conditions, NRF2 levels aretightly controlled by the cytosolic actin-bound repressor, KEAP1(Kelch-like ECH associating protein 1), which binds to NRF2 and targetsit for ubiquitylation and proteasomal degradation via the CuI3-basedE3-ubiquitin ligase complex. Under conditions of oxidative stress, DJ1(PARK7) is activated and stabilizes NRF2 protein by preventing NRF2 frominteracting with KEAP1. Also, modification of reactive cysteines onKEAP1 can cause a conformational change in KEAP1 that alters NRF2binding and promotes NRF2 stabilization. Thus, the levels of NRF2 in thecytosol are low in normal conditions but the system is designed torespond immediately to environmental stress by increasing NRF2 activity.

Inappropriately low NRF2 activity in the face of on-going oxidativestress appears to be a pathological mechanism underlying chronicobstructive pulmonary disease (COPD). This may be a result of an alteredequilibrium between NRF2 regulators with both inappropriate lack ofpositive regulators such as DJ1, and overabundance of negativeregulators such as Keap1 and Bach1. Therefore, restoration of NRF2activity in the lungs of COPD patients should result in repair of theimbalance and mitigation of deleterious processes such as apoptosis ofstructural cells (including alveolar epithelial and endothelial cells)and inflammation. The results of these effects would be enhancedcytoprotection, preservation of lung structure, and structural repair inthe COPD lung, thus slowing disease progression. Therefore, NRF2modulators may treat COPD (Boutten, A., et al. 2011. Trends Mol. Med.17:363-371) and other respiratory diseases, including asthma andpulmonary fibrosis (Cho, H. Y., and Kleeberger, S. R. 2010. Toxicol.Appl. Pharmacol. 244:43-56).

An example of inappropriately low NRF2 activity is found in pulmonarymacrophages from COPD patients. These cells have impaired bacterialphagocytosis compared with similar cells from control patients, and thiseffect is reversed by the addition of NRF2 activators in vitro.Therefore, in addition to the effects mentioned above, restoration ofappropriate NRF2 activity could also rescue COPD exacerbations byreducing lung infections. This is demonstrated by the NRF2 activator,Sulforaphane, which increases the expression of Macrophage Receptor withCollagenous structure (MARCO) by COPD macrophages and alveolarmacrophages from cigarette smoke-exposed mice, thereby improving inthese cells bacterial phagocytosis (Pseudomonas aeruginosa, non-typableHaemophilus influenzae) and bacterial clearance both ex vivo and invivo. (Harvey, C. J., et al. 2011. Sci. Transl. Med. 3:78ra32).

The therapeutic potential of targeting NRF2 in the lung is not limitedto COPD. Rather, targeting the NRF2 pathway could provide treatments forother human lung and respiratory diseases that exhibit oxidative stresscomponents such as chronic asthma and acute asthma, lung diseasesecondary to environmental exposures including but not limited to ozone,diesel exhaust and occupational exposures, fibrosis, acute lunginfection (e.g., viral (Noah, T. L. et al. 2014. PLoS ONE 9(6): e98671),bacterial or fungal), chronic lung infection, al antitrypsin disease,and cystic fibrosis (CF, Chen, J. et al. 2008. PLoS One, 2008;3(10):e3367).

A therapy that targets the NRF2 pathway also has many potential usesoutside the lung and respiratory system. Many of the diseases for whichan NRF2 activator may be useful are autoimmune diseases (psoriasis, IBD,MS), suggesting that an NRF2 activator may be useful in autoimmunediseases in general.

In the clinic, a drug targeting the NRF2 pathway (bardoxolone methyl)has shown efficacy in diabetic patients with diabeticnephropathy/chronic kidney disease (CKD) (Aleksunes, L. M., et al. 2010.J. Pharmacol. Exp. Ther. 335:2-12), though phase III trials with thisdrug in patients with the most severe stage of CKD were terminated.Furthermore, there is evidence to suspect that such a therapy would beeffective in sepsis-induced acute kidney injury, other acute kidneyinjury (AKI) (Shelton, L. M., et al. 2013. Kidney International, June19. doi: 10.1038/ki.2013.248.), and kidney disease or malfunction seenduring kidney transplantation.

In the cardiac area, bardoxolone methyl is currently under investigationin patients with Pulmonary Arterial Hypertension and so a drug targetingNRF2 by other mechanisms may also be useful in this disease area.Oxidative stress is increased in the diseased myocardium, resulting inaccumulation of reactive oxygen species (ROS) which impairs cardiacfunction [Circ (1987) 76(2); 458-468] and increases susceptibility toarrhythmia [J of Mol & Cell Cardio (1991) 23(8); 899-918] by a directtoxic effect of increased necrosis and apoptosis [Circ Res (2000)87(12); 1172-1179]. In a mouse model of pressure overload (TAC), NRF2gene and protein expression is increased during the early stage ofcardiac adaptive hypertrophy but decreased in the later stage ofmaladaptive cardiac remodeling associated with systolic dysfunction[Arterioscler Thromb Vasc Biol (2009) 29(11); 1843-1850; PLOS ONE (2012)7(9); e44899]. In addition, NRF2 activation has been shown to suppressmyocardial oxidative stress as well as cardiac apoptosis, fibrosis,hypertrophy, and dysfunction in mouse models of pressure overload[Arterioscler Thromb Vasc Biol (2009) 29(11); J of Mol & Cell Cardio(2014) 72; 305-315; and 1843-1850; PLOS ONE (2012) 7(9); e44899]. NRF2activation has also been shown to protect against cardiac I/R injury inmice [Circ Res (2009) 105(4); 365-374; J of Mol & Cell Cardio (2010)49(4); 576-586] and reduce myocardial oxidative damage following cardiacI/R injury in rat. Therefore, a drug targeting NRF2 by other mechanismsmay be useful in a variety of cardiovascular diseases including but notlimited to atherosclerosis, hypertension, and heart failure (OxidativeMedicine and Cellular Longevity Volume 2013 (2013), Article ID 104308,10 pages), acute coronary syndrome, myocardial infarction, myocardialrepair, cardiac remodeling, cardiac arrhythmias, heart failure withpreserved ejection fraction, heart failure with reduced ejectionfraction and diabetic cardiomyopathy.

A drug activating the NRF2 pathway could also be useful for treatment ofseveral neurodegenerative diseases including Parkinson's disease (PD),Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) (BrainRes. 2012 March 29; 1446:109-18. 2011.12.064; Epub 2012 January 12.) andmultiple sclerosis (MS). Multiple in vivo models have shown that NRF2 KOmice are more sensitive to neurotoxic insults than their wild-typecounterparts. Treatment of rats with the NRF2 activatortert-butylhydroquinone (tBHQ) reduced cortical damage in rats in acerebral ischemia-reperfusion model, and cortical glutathione levelswere increased in NRF2 wild-type but not KO mice after administration oftBHQ (Shih, A. Y., et al. 2005. J. Neurosci. 25: 10321-10335).Tecfidera™ (dimethyl fumarate), which activates NRF2 among othertargets, is approved in the U.S. to treat relapsing-remitting multiplesclerosis (MS). Activation of NRF2 may also help treat cases ofFriedreich's Ataxia, where increased sensitivity to oxidative stress andimpaired NRF2 activation has been reported (Paupe V., et al, 2009. PLoSOne; 4(1):e4253.

There is preclinical evidence of the specific protective role of theNRF2 pathway in models of inflammatory bowel disease (IBD, Crohn'sDisease and Ulcerative Colitis) and/or colon cancer (Khor, T. O., et al2008. Cancer Prev. Res. (Phila) 1:187-191).

Age-related macular degeneration (AMD) is a common cause of vision lossin people over the age of 50. Cigarette smoking is a major risk factorfor the development of non-neovascular (dry) AMD and perhaps alsoneovascular (wet) AMD. Findings in vitro and in preclinical speciessupport the notion that the NRF2 pathway is involved in the anti-oxidantresponse of retinal epithelial cells and modulation of inflammation inpre-clinical models of eye injury (Schimel, et al. 2011. Am. J. Pathol.178:2032-2043). Fuchs Endothelial Corneal Dystrophy (FECD) is aprogressive, blinding disease characterized by corneal endothelial cellsapoptosis. It is a disease of aging and increased oxidative stressrelated to low levels of NRF2 expression and/or function (Bitar, M. S.,et al. 2012. Invest Ophthalmol. Vis. Sci., Aug. 24, 2012 vol. 53 no. 95806-5813). In addition, an NRF2 activator may be useful in uveitis orother inflammatory eye conditions.

Non-alcoholic steatohepatitis (NASH) is a disease of fat deposition,inflammation, and damage in the liver that occurs in patients who drinklittle or no alcohol. In pre-clinical models, development of NASH isgreatly accelerated in KO mice lacking NRF2 when challenged with amethionine- and choline-deficient diet (Chowdhry S., et al. 2010. FreeRad. Biol. & Med. 48:357-371). Administration of the NRF2 activatorsoltipraz and NK-252 in rats on a choline-deficient L-amino acid-defineddiet significantly attenuated progression of histologic abnormalities,especially hepatic fibrosis (Shimozono R. et al. 2012. MolecularPharmacology, 84:62-70). Other liver diseases that may be amenable toNRF2 modulation are toxin-induced liver disease (e.g.,acetaminophen-induced hepatic disease), viral hepatitis, and cirrhosis(Oxidative Medicine and Cellular Longevity Volume 2013 (2013), ArticleID 763257, 9 page).

Recent studies have also begun to elucidate the role of ROS in skindiseases such as psoriasis. A study in psoriasis patients showed anincrease in serum malondialdehyde and nitric oxide end products and adecrease in erythrocyte-superoxide dismutase activity, catalaseactivity, and total antioxidant status that correlated in each case withdisease severity index (Dipali P. K., et al. Indian J Clin Biochem. 2010October; 25(4): 388-392). Also, an NRF2 modulator may be useful intreating the dermatitis/topical effects of radiation (Schäfer, M. et al.2010. Genes & Devl. 24:1045-1058); and The Immunosuppression due toRadiation Exposure, Kim, J. H. et al, J. Clin. Invest. 2014 February3:124(2):730-41).

There are also data suggesting that an NRF2 activator may be beneficialin preeclampsia, a disease that occurs in 2-5% of pregnancies andinvolves hypertension and proteinuria (Annals of Anatomy—AnatomischerAnzeiqer Volume 196, Issue 5, September 2014, Pages 268-277).

Preclinical data has shown that compounds with NRF2 activating activityare better at reversing high altitude-induced damage than compoundswithout NRF2 activity, using animal and cellular models of AcuteMountain Sickness (Lisk C. et al, 2013, Free Radic Biol Med. October2013; 63: 264-273.)

SUMMARY OF THE INVENTION

In one aspect this invention provides for aryl analogs, pharmaceuticallyacceptable salts thereof, and pharmaceutical compositions containingthem. In particular, the compounds of this invention include a compoundof Formula(I).

In a second aspect, this invention provides for the use of a compound ofFormula (I) as NRF2 regulators.

In another aspect, this invention provides for the use of a compound ofFormula (I) for treating and preventing conditions associated with NRF2imbalance.

In one aspect, this invention provides a pharmaceutical compositioncomprising a compound of the invention according to Formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. Particularly, this invention is directed to apharmaceutical composition for the treatment of an NRF2 regulateddisease or disorder, wherein the composition comprises a compoundaccording to Formula (I), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

In a further aspect, this invention provides for a method of treatingrespiratory and non-respiratory disorders, including COPD, asthma,fibrosis, chronic asthma, acute asthma, lung disease secondary toenvironmental exposures, acute lung infection, chronic lung infection,al antitrypsin disease, cystic fibrosis, autoimmune diseases, diabeticnephropathy, chronic kidney disease, sepsis-induced acute kidney injury,acute kidney injury (AKI), kidney disease or malfunction seen duringkidney transplantation, Pulmonary Arterial Hypertension,atherosclerosis, hypertension, heart failure, acute coronary syndrome,myocardial infarction, myocardial repair, cardiac remodeling, cardiacarrhythmias, heart failure with preserved ejection fraction, heartfailure with reduced ejection fraction, diabetic cardiomyopathy,Parkinson's disease (PD), Alzheimer's disease (AD), Friedreich's Ataxia(FA), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS),inflammatory bowel disease, colon cancer, neovascular (dry) AMD andneovascular (wet) AMD, eye injury, Fuchs Endothelial Corneal Dystrophy(FECD), uveitis or other inflammatory eye conditions, Non-alcoholicSteatohepatitis (NASH), toxin-induced liver disease (e.g.,acetaminophen-induced hepatic disease), viral hepatitis, cirrhosis,psoriasis, dermatitis/topical effects of radiation, immunosuppressiondue to radiation exposure, Preeclampsia, and high altitude sickness,which comprises administering to a human in need thereof, a compound ofFormula (I).

In yet another aspect, this invention provides for the use of a compoundof Formula (I) for the treatment of respiratory and non-respiratorydisorders, including COPD, asthma, fibrosis, chronic asthma and acuteasthma, lung disease secondary to environmental exposures, acute lunginfection, chronic lung infection, al antitrypsin disease, cysticfibrosis, autoimmune diseases, diabetic nephropathy, chronic kidneydisease, sepsis-induced acute kidney injury, acute kidney injury (AKI),kidney disease or malfunction seen during kidney transplantation,Pulmonary Arterial Hypertension, atherosclerosis, hypertension, heartfailure, acute coronary syndrome, myocardial infarction, myocardialrepair, cardiac remodeling, cardiac arrhythmias, heart failure withpreserved ejection fraction, heart failure with reduced ejectionfraction, diabetic cardiomyopathy, Parkinson's disease (PD), Alzheimer'sdisease (AD), Friedreich's Ataxia (FA), amyotrophic lateral sclerosis(ALS), multiple sclerosis (MS), inflammatory bowel disease, coloncancer, neovascular (dry) AMD and neovascular (wet) AMD, eye injury,Fuchs Endothelial Corneal Dystrophy (FECD), uveitis or otherinflammatory eye conditions, Non-alcoholic Steatohepatitis (NASH),toxin-induced liver disease (e.g., acetaminophen-induced hepaticdisease), viral hepatitis, cirrhosis, psoriasis, dermatitis/topicaleffects of radiation, immunosuppression due to radiation exposure,Preeclampsia, and high altitude sickness.

In a further aspect, this invention relates to use of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment of respiratory andnon-respiratory disorders, including COPD, asthma, fibrosis, chronicasthma and acute asthma, lung disease secondary to environmentalexposures, acute lung infection, chronic lung infection, α1 antitrypsindisease, cystic fibrosis, autoimmune diseases, diabetic nephropathy,chronic kidney disease, sepsis-induced acute kidney injury, acute kidneyinjury (AKI), kidney disease or malfunction seen during kidneytransplantation, Pulmonary Arterial Hypertension, atherosclerosis,hypertension, heart failure, acute coronary syndrome, myocardialinfarction, myocardial repair, cardiac remodeling, cardiac arrhythmias,heart failure with preserved ejection fraction, heart failure withreduced ejection fraction, diabetic cardiomyopathy, Parkinson's disease(PD), Alzheimer's disease (AD), Friedreich's Ataxia (FA), amyotrophiclateral sclerosis (ALS), multiple sclerosis (MS), inflammatory boweldisease, colon cancer, neovascular (dry) AMD and neovascular (wet) AMD,eye injury, Fuchs Endothelial Corneal Dystrophy (FECD), uveitis or otherinflammatory eye conditions, Non-alcoholic Steatohepatitis (NASH),toxin-induced liver disease (e.g., acetaminophen-induced hepaticdisease), viral hepatitis, cirrhosis, psoriasis, dermatitis/topicaleffects of radiation, immunosuppression due to radiation exposure,Preeclampsia, and high altitude sickness.

In a further aspect, this invention relates to a compound of Formula (I)or a pharmaceutically acceptable salt thereof, for use in medicaltherapy.

In a further aspect, this invention relates to a compound of Formula (I)or a pharmaceutically acceptable salt thereof, for use in the treatmentof respiratory and non-respiratory disorders, including COPD, asthma,fibrosis, chronic asthma and acute asthma, lung disease secondary toenvironmental exposures, acute lung infection, chronic lung infection,al antitrypsin disease, cystic fibrosis, autoimmune diseases, diabeticnephropathy, chronic kidney disease, sepsis-induced acute kidney injury,acute kidney injury (AKI), kidney disease or malfunction seen duringkidney transplantation, Pulmonary Arterial Hypertension,atherosclerosis, hypertension, heart failure, acute coronary syndrome,myocardial infarction, myocardial repair, cardiac remodeling, cardiacarrhythmias, heart failure with preserved ejection fraction, heartfailure with reduced ejection fraction, diabetic cardiomyopathy,Parkinson's disease (PD), Alzheimer's disease (AD), Friedreich's Ataxia(FA), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS),inflammatory bowel disease, colon cancer, neovascular (dry) AMD andneovascular (wet) AMD, eye injury, Fuchs Endothelial Corneal Dystrophy(FECD), uveitis or other inflammatory eye conditions, Non-alcoholicSteatohepatitis (NASH), toxin-induced liver disease (e.g.,acetaminophen-induced hepatic disease), viral hepatitis, cirrhosis,psoriasis, dermatitis/topical effects of radiation, immunosuppressiondue to radiation exposure, Preeclampsia, and high altitude sickness.

In a further aspect, this invention relates to the use of a compound ofFormula (I) for the treatment of COPD.

In a further aspect, this invention relates to use of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment of COPD.

In a further aspect, this invention relates to a compound of Formula (I)or a pharmaceutically acceptable salt thereof, for use in the treatmentCOPD.

In a further aspect, this invention relates to a method of treating COPDwhich comprises administering to a human in need thereof, a compound ofFormula (I).

In a further aspect, this invention relates to the use of a compound ofFormula (I) for the treatment of heart failure.

In a further aspect, this invention relates to use of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment of heart failure.

In a further aspect, this invention relates to a method of treatingheart failure which comprises administering to a human in need thereof,a compound of Formula (I).

In a further aspect, this invention relates to a compound of Formula (I)or a pharmaceutically acceptable salt thereof, for use in the treatmentof heart failure.

The compounds of Formula (I) and pharmaceutically acceptable saltsthereof may be used in combination with one or more other agents whichmay be useful in the prevention or treatment of allergic disease,inflammatory disease, autoimmune disease, for example; antigenimmunotherapy, anti-histamines, corticosteroids, (e.g., fluticasonepropionate, fluticasone furoate, beclomethasone dipropionate,budesonide, ciclesonide, mometasone furoate, triamcinolone,flunisolide), NSAIDs, leukotriene modulators (e.g., montelukast,zafirlukast, pranlukast), iNOS inhibitors, tryptase inhibitors, IKK2inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such aselastase inhibitors, integrin antagonists (e.g., beta-2 integrinantagonists), adenosine A2a agonists, mediator release inhibitors suchas sodium chromoglycate, 5-lipoxygenase inhibitors (zyflo), DP1antagonists, DP2 antagonists, PI3K delta inhibitors, ITK inhibitors, LP(lysophosphatidic) inhibitors or FLAP (5-lipoxygenase activatingprotein) inhibitors (e.g., sodium3-(3-(tert-butylthio)-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-((5-methylpyridin-2-yl)methoxy)-1H-indol-2-yl)-2,2-dimethylpropanoate),bronchodilators (e.g., muscarinic antagonists, beta-2 agonists),methotrexate, and similar agents; monoclonal antibody therapy such asanti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 andsimilar agents; cytokine receptor therapies e.g. etanercept and similaragents; antigen non-specific immunotherapies (e.g. interferon or othercytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4or CXCR2 antagonists, other cytokine/chemokine agonists or antagonists,TLR agonists and similar agents).

The compounds may also be used in combination with agents for aidingtransplantation including Cyclosporines, Tacrolimus, Mycophenolatemofetil, Prednisone, Azathioprine, Sirolimus, Daclizumab, Basiliximab,or OKT3.

They may also be used in combination with agents for Diabetes: metformin(biguanides), meglitinides, sulfonylureas, DPP-4 inhibitors,Thiazolidinediones, Alpha-glucosidase inhibitors, Amylin mimetics,Incretin mimetics, and insulin.

The compounds may be used in combination with antihypertensives such asdiuretics, ACE inhibitors, ARBS, calcium channel blockers, and betablockers.

In one embodiment, the invention is directed to the use of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, as an activetherapeutic substance. More specifically, this invention provides forthe use of the compounds described herein for the treatment of arespiratory and non-respiratory disorder, specifically, a disease ordisorder recited herein. Accordingly, the invention provides for the useof a compound of Formula (I), or a pharmaceutically acceptable saltthereof, as an active therapeutic substance in the treatment of a humanin need thereof with a respiratory and non-respiratory disorder,specifically, a disease or disorder recited herein. Specifically, theinvention provides for the use of a compound of Formula (I), or apharmaceutically acceptable salt thereof, as an active therapeuticsubstance in the treatment of COPD. Specifically, the invention providesfor the use of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, as an active therapeutic substance in thetreatment of heart failure.

Other aspects and advantages of the present invention are describedfurther in the following detailed description of the preferredembodiments thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides for compounds of Formula (I):

wherein:B is benzotriazolyl, phenyl, triazolopyridinyl, or —(CH₂)₂ triazolyleach of which may be unsubstituted or substituted by 1, 2, or 3substituents independently chosen from—C₁₋₃alkyl, —O—C₁₋₃alkyl, CN, —(CH₂)₂—O—(CH₂)₂—OR₄ and halo; D is—C(O)OH, —C(O)NHSO₂CH₃, —SO₂NHC(O)CH₃,5-(trifluoromethyl)-4H-1,2,4-triazol-2-yl, or tetrazolyl;R₁ is independently hydrogen, C₁₋₃alkyl, F, C₃₋₆spirocycloalkyl,oxetane, or the two R, groups together with the carbon to which they areattached form a cyclopropyl group;R₂ is hydrogen, methyl, CF₃, or halo;R₄ is hydrogen or —C₁₋₃alkyl;Linker is —CH₂—, —CH₂—N(-cyclopropyl)-CH₂—, —CH₂—N(CH₃)—CH₂— or—N—(CH₃)—CH₂—;A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl,piperidinyl, tetrahydrobenzazepinyl, phenyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, tetrahydropyrrolopyrazinyl, imidazopyridinyl,pyridyl, benzimidazolyl, tetrahydrobenzodiazepinyl, piperidopyrimidinyl,dioxidotetrahydrothiophenyl, tetrahydroimidazodiazepinyl, pyrrolidinyl,oxazepane or morpholinyl;All of which may be unsubstituted or substituted by 1, 2, or 3substituents independently chosen from: —C₁₋₃alkyl, C₃-6spirocycloalkyl,halo, CN, —O—C₁₋₃alkyl, —CH₂—O—CH₃, and OH;And the piperidinyl may additionally be independently substituted bypyrazolyl, —CH₂pyrazolyl, or oxadiazolyl each of which may be furtherindependently substituted by —C₁₋₃alkyl, or, when A is piperidinyl, itmay be substituted by —SO₂R, wherein R is C₁₋₃alkyl, phenyl orC₃₋₇cycloalkyl;And the oxazepane may additionally be independently substituted by 1 or2 of —C₁₋₃alkyl or —C₃₋₇cycloalkyl;And the morpholinyl may additionally be substituted by a phenyl whichitself may be independently substituted by C₁₋₃ alkyl or —O— C₁₋₃ alkyl;And the pyrrolidinyl may be additionally substituted by a triazolylgroup which itself is may be substituted by —C₁₋₃alkyl;And the imidazolyl, triazolyl, pyrazolyl, and tetrazolyl groups may beadditionally independently substituted by —CH₂—C₄₋₇ cycloalkyl,—CH₂—C₅₋₇heterocycloalkyl, —CH₂— azabicycloheptanyl, —CH₂-oxepane, or—CH₂-azabicyclohexanyl, all of which, including the —CH₂—, may befurther substituted independently by 1 or 2 of —C₁₋₃ alkyl or F; andX is independently CH or N;or a pharmaceutically acceptable salt thereof.

“Alkyl” refers to a monovalent saturated hydrocarbon chain having thespecified number of carbon member atoms. For example, C₁₋₄alkyl refersto an alkyl group having from 1 to 4 carbon member atoms. Alkyl groupsmay be straight or branched. Representative branched alkyl groups haveone, two, or three branches. Alkyl includes methyl, ethyl, propyl,(n-propyl and isopropyl), and butyl (n-butyl, isobutyl, s-butyl, andt-butyl).

“Cycloalkyl” refers to a monovalent saturated or unsaturated hydrocarbonring having the specified number of carbon member atoms. For example,C₃₋₆cycloalkyl refers to a cycloalkyl group having from 3 to 6 carbonmember atoms. Unsaturated cycloalkyl groups have one or morecarbon-carbon double bonds within the ring. Cycloalkyl groups are notaromatic. Cycloalkyl includes cyclopropyl, cyclopropenyl, cyclobutyl,cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.

“C₅₋₇ heterocycloalkyl” refers to pyrrolidine, piperidine, morpholine,azepane, 1,4-oxazepane, 1,4-thiazepane, 1,4-thiazepane 1-oxide,1,4-thiazepane 1,1-dioxide, thiomorpholine, thiomorpholine 1-oxide, andthiomorpholine 1,1-dioxide.

When used herein, the terms ‘halogen’ and ‘halo’ include fluorine,chlorine, bromine and iodine, and fluoro, chloro, bromo, and iodo,respectively.

“Substituted” in reference to a group indicates that one or morehydrogen atom attached to a member atom within the group is replacedwith a substituent selected from the group of defined substituents. Itshould be understood that the term “substituted” includes the implicitprovision that such substitution be in accordance with the permittedvalence of the substituted atom and the substituent and that thesubstitution results in a stable compound (i.e. one that does notspontaneously undergo transformation such as by rearrangement,cyclization, or elimination and that is sufficiently robust to surviveisolation from a reaction mixture). When it is stated that a group maycontain one or more substituents, one or more (as appropriate) memberatoms within the group may be substituted. In addition, a single memberatom within the group may be substituted with more than one substituentas long as such substitution is in accordance with the permitted valenceof the atom. Suitable substituents are defined herein for eachsubstituted or optionally substituted group.

The term “independently” means that where more than one substituent isselected from a number of possible substituents, those substituents maybe the same or different. That is, each substituent is separatelyselected from the entire group of recited possible substituents.

The invention also includes various isomers of the compounds of Formula(I) and mixtures thereof. “Isomer” refers to compounds that have thesame composition and molecular weight but differ in physical and/orchemical properties. The structural difference may be in constitution(geometric isomers) or in the ability to rotate the plane of polarizedlight (stereoisomers). The compounds according to Formula (I) containone or more asymmetric centers, also referred to as chiral centers, andmay, therefore, exist as individual enantiomers, diastereomers, or otherstereoisomeric forms, or as mixtures thereof. All such isomeric formsare included within the present invention, including mixtures thereof.

Chiral centers may also be present in a substituent such as an alkylgroup. Wherethe stereochemistry of a chiral center present in Formula(I), or in any chemical structure illustrated herein, is not specifiedthe structure is intended to encompass any stereoisomer and all mixturesthereof. Thus, compounds according to Formula (I) containing one or morechiral centers may be used as racemic mixtures, enantiomericallyenriched mixtures, or as enantiomerically pure individual stereoisomers.

Individual stereoisomers of a compound according to Formula (I) whichcontain one or more asymmetric centers may be resolved by methods knownto those skilled in the art. For example, such resolution may be carriedout (1) by formation of diastereoisomeric salts, complexes or otherderivatives; (2) by selective reaction with a stereoisomer-specificreagent, for example by enzymatic oxidation or reduction; or (3) bygas-liquid or liquid chromatography in a chiral environment, forexample, on a chiral support such as silica with a bound chiral ligandor in the presence of a chiral solvent. The skilled artisan willappreciate that where the desired stereoisomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step is required to liberate the desired form. Alternatively,specific stereoisomers may be synthesized by asymmetric synthesis usingoptically active reagents, substrates, catalysts or solvents, or byconverting one enantiomer to the other by asymmetric transformation.

As used herein, “pharmaceutically acceptable” refers to those compounds,materials, compositions, and dosage forms which are, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhuman beings and animals without excessive toxicity, irritation, orother problem or complication, commensurate with a reasonablebenefit/risk ratio.

The skilled artisan will appreciate that pharmaceutically acceptablesalts of the compounds according to Formula (I) may be prepared. Thesepharmaceutically acceptable salts may be prepared in situ during thefinal isolation and purification of the compound, or by separatelytreating the purified compound in its free acid or free base form with asuitable base or acid, respectively.

In certain embodiments, compounds according to Formula (I) may containan acidic functional group and are, therefore, capable of formingpharmaceutically acceptable base addition salts by treatment with asuitable base. Examples of such bases include a) hydroxides, carbonates,and bicarbonates of sodium, potassium, lithium, calcium, magnesium,aluminum, and zinc; and b) primary, secondary, and tertiary aminesincluding aliphatic amines, aromatic amines, aliphatic diamines, andhydroxy alkylamines such as methylamine, ethylamine,2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine,ethanolamine, diethanolamine, and cyclohexylamine.

In certain embodiments, compounds according to Formula (I) may contain abasic functional group and are therefore capable of formingpharmaceutically acceptable acid addition salts by treatment with asuitable acid. Suitable acids include pharmaceutically acceptableinorganic acids and organic acids. Representative pharmaceuticallyacceptable acids include hydrogen chloride, hydrogen bromide, nitricacid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid,hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid,valeric acid, maleic acid, acrylic acid, fumaric acid, succinic acid,malic acid, malonic acid, tartaric acid, citric acid, salicylic acid,benzoic acid, tannic acid, formic acid, stearic acid, lactic acid,ascorbic acid, methylsulfonic acid, p-toluenesulfonic acid, oleic acid,lauric acid, and the like.

As used herein, the term “a compound of Formula (I)” or “the compound ofFormula (I)” refers to one or more compounds according to Formula (I).The compound of Formula (I) may exist in solid or liquid form. In thesolid state, it may exist in crystalline or noncrystalline form, or as amixture thereof. The skilled artisan will appreciate thatpharmaceutically acceptable solvates may be formed from crystallinecompounds wherein solvent molecules are incorporated into thecrystalline lattice during crystallization. Solvates may involvenon-aqueous solvents such as, but not limited to, ethanol, isopropanol,DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involvewater as the solvent that is incorporated into the crystalline lattice.Solvates wherein water is the solvent incorporated into the crystallinelattice are typically referred to as “hydrates.” Hydrates includestoichiometric hydrates as well as compositions containing variableamounts of water. The invention includes all such solvates.

The skilled artisan will further appreciate that certain compounds ofthe invention that exist in crystalline form, including the varioussolvates thereof, may exhibit polymorphism (i.e. the capacity to occurin different crystalline structures). These different crystalline formsare typically known as “polymorphs.” The invention includes all suchpolymorphs. Polymorphs have the same chemical composition but differ inpacking, geometrical arrangement, and other descriptive properties ofthe crystalline solid state. Polymorphs, therefore, may have differentphysical properties such as shape, density, hardness, deformability,stability, and dissolution properties. Polymorphs typically exhibitdifferent melting points, IR spectra, and X-ray powder diffractionpatterns, which may be used for identification. The skilled artisan willappreciate that different polymorphs may be produced, for example, bychanging or adjusting the reaction conditions or reagents, used inmaking the compound. For example, changes in temperature, pressure, orsolvent may result in polymorphs. In addition, one polymorph mayspontaneously convert to another polymorph under certain conditions.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in Formula (I) and following, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention and pharmaceutically acceptable saltsthereof include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulphur, fluorine, iodine, and chlorine, such as ²H, ³H,¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I.

Compounds of the present invention and pharmaceutically acceptable saltsof said compounds that contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of the present invention.Isotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H, ¹⁴C are incorporated,are useful in drug and/or substrate tissue distribution assays.Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. ¹¹C and ¹⁸Fisotopes are particularly useful in PET (positron emission tomography),and ¹²⁵I isotopes are particularly useful in SPECT (single photonemission computerized tomography), all useful in brain imaging. Further,substitution with heavier isotopes such as deuterium, i.e., ²H, canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of Formula (I) and following of thisinvention can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples below, by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent.

Representative Embodiments

In one embodiment:

B is benzotriazolyl, phenyl, triazolopyridinyl, or —(CH₂)₂ triazolyleach of which may be unsubstituted or substituted by 1, 2, or 3substituents independently chosen from —C₁₋₃alkyl, —O—C₁₋₃alkyl, CN,—(CH₂)₂—O—(CH₂)₂—OR₄ and halo;D is —C(O)OH, —C(O)NHSO₂CH₃, —SO₂NHC(O)CH₃,5-(trifluoromethyl)-4H-1,2,4-triazol-2-yl, or tetrazolyl;R₁ is independently hydrogen, C₁₋₃alkyl, F, C₃₋₆spirocycloalkyl,oxetane, or the two R, groups together with the carbon to which they areattached form a cyclopropyl group;R₂ is hydrogen, methyl, CF₃, or halo;R₄ is hydrogen or —C₁₋₃alkyl;Linker is —CH₂—, —CH₂—N(-cyclopropyl)-CH₂—, —CH₂—N(CH₃)—CH₂— or—N—(CH₃)—CH₂—;A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl,piperidinyl, tetrahydrobenzazepinyl, phenyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, tetrahydropyrrolopyrazinyl, imidazopyridinyl,pyridyl, benzimidazolyl, tetrahydrobenzodiazepinyl, piperidopyrimidinyl,dioxidotetrahydrothiophenyl, tetrahydroimidazodiazepinyl, pyrrolidinyl,oxazepane or morpholinyl;All of which may be unsubstituted or substituted by 1, 2, or 3substituents independently chosen from: —C₁₋₃alkyl, C₃₋₆spirocycloalkyl,halo, CN, —O—C₁₋₃alkyl, —CH₂—O—CH₃, and OH;And the piperidinyl may additionally be independently substituted bypyrazolyl, —CH₂pyrazolyl, or oxadiazolyl each of which may be furtherindependently substituted by —C₁₋₃alkyl, or, when A is piperidinyl, itmay be substituted by —SO₂R, wherein R is —C₁₋₃alkyl, phenyl orC₃₋₇cycloalkyl;And the oxazepane may additionally be independently substituted by 1 or2 of —C₁₋₃alkyl or —C₃₋₇cycloalkyl;And the morpholinyl may additionally be substituted by a phenyl whichitself may be independently substituted by —C₁₋₃alkyl or —O—C₁₋₃alkyl;And the pyrrolidinyl may be additionally substituted by a triazolylgroup which itself is may be substituted by —C₁₋₃alkyl;And the imidazolyl, triazolyl, pyrazolyl, and tetrazolyl groups may beadditionally independently substituted by —CH₂—C₄₋₇ cycloalkyl,—CH₂—C₅₋₇heterocycloalkyl, —CH₂— azabicycloheptanyl, —CH₂-oxepane, or—CH₂-azabicyclohexanyl, all of which, including the —CH₂—, may befurther substituted independently by 1 or 2 of —C₁₋₃ alkyl or F; andX is independently CH or N;or a pharmaceutically acceptable salt thereof.

In another embodiment:

B is benzotriazolyl or —(CH₂)₂ triazolyl each of which may beunsubstituted or substituted by 1, 2, or 3 substituents independentlychosen from: —C₁₋₃alkyl and halo;D is —C(O)OH, —C(O)NHSO₂CH₃, or tetrazolyl;R₁ is independently hydrogen or methyl or the two R, groups togetherwith the carbon to which they are attached form a cyclopropyl group;R₂ is methyl or halo;

Linker is —CH₂—;

A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl,piperidinyl, tetrahydrobenzazepinyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, or tetrahydrobenzodiazepinyl;All of which may be unsubstituted or substituted by 1, 2, or 3substituents independently chosen from —C₁₋₃ alkyl, halo, CN, or—OC₁₋₃alkyl;And the piperidinyl may additionally be substituted by pyrazolyl oroxadiazolyl each of which may be further substituted by —C₁₋₃alkyl or,when A is piperidinyl, it may be substituted by —SO₂R, wherein R is—C₁₋₃alkyl, phenyl or C₃₋₇cycloalkyl;And the imidazolyl, triazolyl, pyrazolyl, and tetrazolyl groups may beadditionally independently substituted by —CH₂—C₄₋₇ cycloalkyl,—CH₂-oxepane or a —CH₂—C₅₋₇; andX is independently CH or N;or a pharmaceutically acceptable salt thereof.

In yet another embodiment:

B is benzotriazolyl, or —(CH₂)₂ triazolyl each of which may beunsubstituted or substituted by 1, 2, or 3 substituents independentlychosen from —C₁₋₃alkyl and halo;

D is —C(O)OH;

R₁ is independently hydrogen or methyl or the two R, groups togetherwith the carbon to which they are attached form a cyclopropyl group;R₂ is methyl or halo;

Linker is —CH₂—;

A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl,piperidinyl, tetrahydrobenzazepinyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, or tetrahydrobenzodiazepinyl;All of which may be unsubstituted or substituted by 1, 2, or 3substituents independently chosen from —C₁₋₃ alkyl, halo, CN, or—OC₁₋₃alkyl;And the piperidinyl may additionally be substituted by pyrazolyl oroxadiazolyl each of which may be further substituted by —C₁₋₃alkyl or,when A is piperidinyl, it may be substituted by —SO₂R, wherein R is—C₁₋₃alkyl, phenyl or C₃₋₇cycloalkyl;And the imidazolyl, triazolyl, pyrazolyl, and tetrazolyl groups may beadditionally independently substituted by —CH₂—C₄₋₇ cycloalkyl,—CH₂-oxepane or a —CH₂—C₅₋₇; and

X is CH;

or a pharmaceutically acceptable salt thereof.

In another embodiment:

B is benzotriazolyl unsubstituted or substituted by 1, 2, or 3substituents independently chosen from —C₁₋₃alkyl and halo;

D is —C(O)OH;

R₁ is independently hydrogen or C₁₋₃alkyl;R₂ is methyl or chloro;

Linker is —CH₂—;

A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl,piperidinyl, tetrahydrobenzazepinyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, or tetrahydrobenzodiazepinyl;All of which may be unsubstituted or substituted by 1, 2, or 3substituents independently chosen from —C₁₋₃ alkyl, halo, CN, or—OC₁₋₃alkyl;And the piperidinyl may additionally be substituted by pyrazolyl oroxadiazolyl each of which may be further substituted by —C₁₋₃alkyl or,when A is piperidinyl, it may be substituted by —SO₂R, wherein R is—C₁₋₃alkyl, phenyl or C₃₋₇cycloalkyl;And the imidazolyl, triazolyl, pyrazolyl, and tetrazolyl groups may beadditionally independently substituted by —CH₂—C₄₋₇ cycloalkyl,—CH₂-oxepane or a —CH₂—C₅₋₇; and

X is CH;

or a pharmaceutically acceptable salt thereof.

In a further embodiment:

B is triazolopyridinyl which may be unsubstituted or substituted by 1,2, or 3 substituents which are —C₁₋₃alkyl;

D is —C(O)OH;

R₁ is independently hydrogen or C₁₋₃alkyl;R₂ is methyl or chloro;

Linker is —CH₂—;

A is tetrahydrobenzoxazepinyl which may be unsubstituted or substitutedby 1, 2, or 3 substituents which are —C₁₋₃alkyl; and

X is CH;

or a pharmaceutically acceptable salt thereof.

In yet another embodiment:

B is —(CH₂)₂ triazolyl which may be unsubstituted or substituted by 1,2, or 3 substituents which are —C₁₋₃alkyl;

D is —C(O)OH;

R₁ is independently hydrogen or methyl;R₂ is methyl or halo;

Linker is —CH₂—;

A is tetrahydrobenzoxazepinyl or imidazolyl;Each of which may be unsubstituted or substituted by 1, 2, or 3substituents which are —C₁₋₃ alkyl;And the imidazolyl may be additionally substituted by —CH₂—C₄₋₇cycloalkyl; and

X is CH;

or a pharmaceutically acceptable salt thereof.

In still another embodiment:

B is benzotriazolyl which may be unsubstituted or substituted by 1, 2,or 3 substituents independently chosen from —C₁₋₃alkyl and halo;

D is —C(O)OH;

R₁ is independently hydrogen or C₁₋₃alkyl;R₂ is methyl or chloro;

Linker is —CH₂—;

A is tetrahydrobenzoxazepinyl, imidazolyl or piperidinyl;All of which may be unsubstituted or substituted by 1, 2, or 3substituents independently chosen from —C₁₋₃alkyl, halo and OH;And the piperidinyl may additionally be substituted by pyrazolyl and—CH₂pyrazolyl;And the imidazolyl may be additionally optionally substituted by—CH₂—C₄₋₇ cycloalkyl, —CH₂—C₅₋₇heterocycloalkyl, each of which,including the —CH₂—, may be further substituted by 1 or 2 of—C₁₋₃ alkyl; and

X is CH;

or a pharmaceutically acceptable salt thereof.

It is to be understood that the present invention covers allcombinations of particular groups described hereinabove.

Specific examples of compounds of the present invention include thefollowing:

-   3-(3-((2,3-Dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)    methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, trifluoroacetic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, trifluoroacetic acid salt;-   Ethyl    3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoate,    trifluoroacetic acid salt;-   5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)pentanoic    acid, trifluoroacetic acid salt;-   (3S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, trifluoroacetic acid salt;-   (3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, trifluoroacetic acid salt;-   3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((7-methoxy-4-methyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid, formic acid salt;-   Ammonium    3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate;-   Ammonium    3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-(5-isopropyl-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)methyl)-4-methylphenyl)propanoate;-   Ammonium    3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-isopropyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methyl)-4-methylphenyl)    propanoate;-   Ammonium    3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-(5-ethyl-1,2,4-oxadiazol-3-yl)piperidin-1-yl)methyl)-4-methylphenyl)    propanoate;-   Ammonium    3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methyl)-4-methylphenyl)    propanoate;-   Ammonium3-(3-((7-cyano-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate;-   Ammonium    3-(3-(((2-bromobenzyl)(methyl)amino)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate;-   Ammonium    3-(3-(((4-bromobenzyl)(methyl)amino)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate-   Ammonium    3-(3-(((3-bromobenzyl)(methyl)amino)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-methyl-2-(p-tolyl)morpholino)methyl)phenyl)propanoate,    formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   3-(3-((cyclopropyl(4-methoxybenzyl)amino)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, formic acid salt;-   3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((3-(4-methoxyphenyl)morpholino)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid, trifluoroacetic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid, trifluoroacetic acid salt;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid, formic acid salt;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9-fluoro-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid;-   (S)-3-(3-(((R)-8-Chloro-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   (S)-Methyl    3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate,    formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((9-fluoro-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid;-   3-(3-((6,7-Dihydro-5H-imidazo[1,5-a][1,4]diazepin-8(9H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate,    Sodium salt;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid, trifluoroacetic acid salt;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid, trifluoroacetic acid salt;-   (R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-6-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid, formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-7-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid, formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid, formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid, formic acid salt;-   (2R,3S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic    acid, formic acid salt;-   (2S,3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic    acid;-   (2R,3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic    acid;-   (2S,3S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic    acid;-   (2R,3S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic    acid;-   (3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-7-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic    acid, trifluoroacetic acid salt;-   (R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   3-(3-((2,3-Dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid, formic acid salt;-   3-(3-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, formic acid salt-   3-(3-((2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, trifluoroacetic acid salt;-   3-(3,7-Dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, trifluoroacetic acid salt;-   3-(3,7-Dimethyl-3H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, trifluoroacetic acid salt;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   (R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   (S)-3-(1-Ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, 0.5 formic acid salt;-   (S)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   (S)-3-(4-Chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid,-   hydrochloride;-   (S)-3-(4-Chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   (R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((7-fluoro-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, 0.7 formic acid salt;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, Sodium salt;-   (R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((8-fluoro-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   (R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, Sodium salt;-   (R)-3-(4-Chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((7-fluoro-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, 1.5 formic acid salt;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((8-fluoro-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   (S)-3-(3-((2,2-Dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   (R)-3-(3-((2,2-Dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, Hydrochloride;-   (S)-3-(4-Chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate,    Sodium salt;-   (R)-3-(4-Chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate,    Sodium salt;-   (3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, trifluoroacetic acid salt;-   (S)-3-(3-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, formic acid salt;-   3-(3-((2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, formic acid salt;-   3-(3-((2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, formic acid salt-   3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-propyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoic    acid, formic acid salt;-   3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-isopropyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-(methoxymethyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoic    acid, trifluoroacetic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   Ammonium    3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate;-   Ammonium    3-(3-(((R)-7-chloro-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-7-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   Ammonium    3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-7-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate;-   3-(3-((8-Bromo-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-6-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-8-methoxy-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   Ammonium    3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-8-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-7-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   3-(3-((6-Chloro-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   3-(3-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   3-(3-(((S)-8-bromo-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((R)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoic    acid, formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-fluoro-3-(((S)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoic    acid, formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((S)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoic    acid, formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((S)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoic    acid, formic acid salt;-   3-(4-Chloro-3-((2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, formic acid salt;-   (3S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic    acid;-   Ammonium    (2S,3R)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate;-   (3R)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic    acid;-   Ammonium    3-(3-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate;-   3-(3-((4,5-Dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   Ammonium    3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((4,4-dimethyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoate;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((4-ethyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((4-ethyl-8-fluoro-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,8-trimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoic    acid, formic acid salt;-   (S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   (R)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1-ethyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid, formic acid salt;-   (2R)-4-(5-(1-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-(1H-tetrazol-5-yl)ethyl)-2-methylbenzyl)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine,    formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid, lithium salt;-   3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(4-fluoro-2-methylphenyl)-2,2-dimethylpropanoic    acid, formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   3-(2,4-difluorophenyl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, formic acid salt;-   5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoic    acid;-   (S)-3-(3-((2-(Cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate,    sodium salt;-   (S)-3-(3-((2-(Azepan-1-ylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate,    Sodium salt;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate,    sodium salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((2-(piperidin-1-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoate,    sodium salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((2-(pyrrolidin-1-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoate,    sodium salt;-   (R)-3-(3-((2-(Cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate,    sodium salt;-   3-(3-((2-(Cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   3-(3-((1-(Cyclohexylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)propanoic    acid;-   3-(3-((2-(Cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)pentanoic    acid;-   3-(3-((2-(Cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylcyclohexyl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)propanoic    acid;-   Ammonium    3-(3-((2-(1-cyclohexylethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate;-   3-(3-((1-(Cyclohexylmethyl)-1H-tetrazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, hydrochloride salt;-   3-(3-((2-(Cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)pentanoic    acid;-   3-(3-((2-(Cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(4-fluoro-2-methylphenyl)propanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)propanoic    acid;-   3-(3-((4-(Cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   3-(3-((3-(Cyclohexylmethyl)-5-methyl-1H-1,2,4-triazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   3-(3-((2-((1,4-Oxazepan-4-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((2-((4-methylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)propanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid, formic acid salt;-   3-(3-((2-(Azepan-1-ylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid, trifluoroacetic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((2-(morpholinomethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoic    acid, trifluoroacetic acid salt;-   3-(3-((2-(Cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid, trifluoroacetic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((2-(((R)-2-methylmorpholino)methyl)-1H-imidazol-1-yl)methyl)phenyl)propanoic    acid, trifluoroacetic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)propanoic    acid, trifluoroacetic acid salt;-   3-(3-((2-(Cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, formic acid salt;-   3-(3-((2-(Azepan-1-ylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, formic acid salt;-   3-(3-((2-(Cyclopentylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   3-(3-((2-((4,4-Difluoropiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((2-(piperidin-1-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoic    acid;-   3-(3-((2-(Azepan-1-ylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid, 0.3 formic acid salt;-   (3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2-methylpropanoic    acid, trifluoroacetic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-(pyrrolidin-1-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoic    acid, formic acid salt-   3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-(piperidin-1-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoic    acid, trifluoroacetic acid salt;-   3-(3-((2-(cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, Trifluoroacetic acid salt;-   3-(3-((2-(7-Azabicyclo[2.2.1]heptan-7-ylmethyl)-1H-imidazol-1l-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid, trifluoroacetic acid salt;-   3-(3-((2-(8-Azabicyclo[3.2.1]octan-8-ylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid, trifluoroacetic acid salt;-   (3R)-3-(3-((3-(1H-Pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid (isomer 1);-   (3R)-3-(3-((3-(1H-Pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid (isomer 2);-   (3S)-3-(3-((3-(1H-Pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid (isomer 1);-   3-(3-((3-(1H-Pyrazol-1-yl)piperidin-1-yl)methyl)-4-chlorophenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, formic acid salt;-   3-(4-chloro-3-((3-hydroxypiperidin-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   3-(3-((3-(1H-Pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoic    acid, formic acid salt;-   3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-chlorophenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, formic acid salt;-   3-(3-((6,7-Dihydro-5H-imidazo[1,5-a][1,4]diazepin-8(9H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid, Sodium salt;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((7-methoxy-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, 0.5 Formic acid salt;-   (R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((7-methoxy-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   (R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((8-methoxy-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((8-methoxy-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   (R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, 0.5 Formic acid salt;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid, 0.5 Formic acid salt;-   rel-(R)-3-(3-((7-Cyano-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   rel-(S)-3-(3-((7-Cyano-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   rel-(R)-3-(3-((8-Cyano-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   rel-(S)-3-(3-((8-Cyano-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   (R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,7-trimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoic    acid;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,7-trimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoic    acid;-   (R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((9-fluoro-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((9-fluoro-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   (R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,8-trimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoic    acid;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,8-trimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoic    acid;-   rel-(R)-3-(3-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)    propanoic acid;-   rel-(S)-3-(3-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)    propanoic acid;-   (S)-3-(3-(((S)-3-(1H-Pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(3-(((R)-3-(1H-Pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((3-(phenylsulfonyl)piperidin-1-yl)methyl)phenyl)propanoic    acid;-   3-(3-((3-(Cyclohexylsulfonyl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-N-(methylsulfonyl)propanamide;-   (S)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   (2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic    acid;-   (2R,3S)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic    acid;-   (2R,3S)-3-(1-Ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic    acid;-   (2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic    acid-   Sodium salt;-   (2R,3S)-3-(4-Chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic    acid;-   (2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic    acid;-   (2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic    acid, Trifluoroacetic acid salt;-   (2S,3R)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate,    Sodium salt;-   (2S,3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic    acid, 0.1 formic acid salt;-   (2S,3R)-3-(3-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic    acid;-   (2S,3R)-3-(3-((2,2-Dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic    acid, 2 Trifluoroacetic acid salt;-   (2S,3R)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methyl-3-(4-methyl-3-((2-(piperidin-1-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoic    acid;-   (2R,3S)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic    acid;-   (2R,3S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic    acid, 0.2 formic acid salt;-   (R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid, 0.5 Ethanol;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-N-(methylsulfonyl)propanamide,    Trifluoroacetic acid salt;-   rel-(R)-3-(3-((2,2-Dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid [enantiomer A (first to elute from SFC)];-   rel-(R)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   (2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic    acid, 2 Trifluoroacetic acid salt;-   (2R,3S)-3-(7-Chloro-1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic    acid;-   (2R,3S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methyl-3-(4-methyl-3-((2-(piperidin-1-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoic    acid;-   1-((1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)methyl)cyclopropanecarboxylic    acid, Trifluoroacetic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoic    acid, formic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic    acid, Trifluoroacetic acid salt;-   3-(5-((2-(Cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-6-methylpyridin-3-yl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid, Trifluoroacetic acid salt;-   (3S)-3-(3-((3-((1H-Pyrazol-1-yl)methyl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoic    acid;-   5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoic    acid;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid, Trifluoroacetate;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid, Trifluoroacetate;-   5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoic    acid, 3.2 Trifluoroacetic acid salt;-   3-(3-((2,2-Dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoic    acid;-   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-6-fluoro-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid;-   3-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoic    acid;-   5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoic    acid, 0.20 formic acid salt;-   5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2-methylpentanoic    acid, Trifluoroacetic acid salt;-   5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2-methylpentanoic    acid, Trifluoroacetic acid salt;-   3-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoic    acid, Trifluoroacetic acid salt;-   3-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoic    acid;-   Benzyl    3-(4-chloro-3-((2-(cycloheptylmethyl)-1H-imidazol-1-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoate;-   3-(4-Chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoic    acid;-   3-(4-Chloro-3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoic    acid;-   5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)pentanoic    acid;-   3-(4-Chloro-3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoic    acid;-   5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-N-(methylsulfonyl)pentanamide;-   (S)-3-(3-((2-(Cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   3-(4-Chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(4-Chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(4-Chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid;-   (3S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic    acid;-   rel-(S)-3-(3-((1-(cycloheptylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   rel-(R)-3-(3-((1-(cycloheptylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   3-(3-((3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclopropan]-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   3-(3-((3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclobutan]-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((2-(oxepan-4-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoic    acid;-   3-(3-((7-Cyclopropyl-2-ethyl-1,4-oxazepan-4-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic    acid;-   3-(3-((2-((4-Ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoic    acid;-   3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoic    acid;-   5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoic    acid;-   5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoic    acid;-   5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoic    acid;-   5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoic    acid;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate;-   (S)-((Diphenoxyphosphoryl)oxy)methyl    3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate;-   3-((S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoyl)thiazolidin-2-one,    Trifluoroacetic acid salt;-   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate;-   (S)-ethyl    3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2.3-dihydropyrido[2,3-ft][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)    propionate;-   (S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   (S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-fluorophenyl)propanoic    acid;-   rel-(R)-3-(1,4-dimethyl-1H-benzo[d]-[1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-fluorophenyl)-propanoic    acid (isomer 1);-   rel-(R)-3-(4-chloro-3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid (isomer 1);-   (S)-3-(4-chloro-3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid; and-   (S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;    or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention is a compound of Formula (I) which is(S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2.3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propionate,or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention is a compound of Formula (I) whichis:

-   (S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid;-   (S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-fluorophenyl)propanoic    acid;-   rel-(R)-3-(1,4-dimethyl-1H-benzo[d]-[1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-fluorophenyl)-propanoic    acid (isomer 1);-   rel-(R)-3-(1,4-dimethyl-1H-benzo[d]-[1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-fluorophenyl)-propanoic    acid (isomer 1);-   rel-(R)-3-(4-chloro-3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid (isomer 1);-   (S)-3-(4-chloro-3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic    acid; and-   (S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic    acid,

or a pharmaceutically acceptable salt thereof.

Compound Preparation

The skilled artisan will appreciate that if a substituent describedherein is not compatible with the synthetic methods described herein,the substituent may be protected with a suitable protecting group thatis stable to the reaction conditions. The protecting group may beremoved at a suitable point in the reaction sequence to provide adesired intermediate or target compound. Suitable protecting groups andthe methods for protecting and de-protecting different substituentsusing such suitable protecting groups are well known to those skilled inthe art; examples of which may be found in T. Greene and P. Wuts,Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY(1999). In some instances, a substituent may be specifically selected tobe reactive under the reaction conditions used. Under thesecircumstances, the reaction conditions convert the selected substituentinto another substituent that is either useful as an intermediatecompound or is a desired substituent in a target compound.

The synthesis of the compounds of the general Formula (I) andpharmaceutically acceptable derivatives and salts thereof may beaccomplished as outlined below in Schemes 1-30. In the followingdescription, the groups are as defined above for compounds of Formula(I) unless otherwise indicated. Abbreviations are as defined in theExamples section. Starting materials are commercially available or aremade from commercially available starting materials using methods knownto those skilled in the art.

Scheme 1 shows a general scheme for the preparation of5-bromo-4-methyl-1-methyl-1H-benzo[d][1,2,3]triazole. Starting withcommercially available 1-fluoro-3-methyl-2-nitrobenzene, brominationwith NBS provides intermediate 2. Displacement of the fluoride using anappropriate amine followed by zinc metal reduction of the nitro to theaniline and diazotization and cyclization provides the required triazole3. Completion of the fully elaborated analog can be accomplished in afashion analogous to that shown in scheme 23.

Scheme 2 shows a general scheme for the preparation of5-bromo-7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazole. Starting withcommercially available 2-amino-3-nitrophenol, methylation of the phenolusing K₂CO₃ and MeI (step a) provides intermediate 2 which can bebrominated with NBS (step c). Methylation of the aniline (step d)followed by reduction of the nitro group (step d) and diazotization andcyclization (step e) provide the required triazole 5. Completion of thefully elaborated analog can be accomplished in a fashion analogous tothat shown in Scheme 23.

Scheme 3 shows a general scheme for the preparation of5-bromo-7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazole. This two stepprocess starts with iodination at C₇ of5-bromo-1,4-dimethyl-1H-benzo[d][1,2,3]triazole. Copper mediatedreplacement of the iodide with methanol provides the desired material.Completion of the fully elaborated analog can be accomplished in afashion analogous to that shown in Scheme 23.

Scheme 4 represents a general scheme for the preparation of3-(1H-pyrazol-1-yl)piperidine used in the invention. In this, tert-butyl3-hydroxypiperidine-1-carboxylate depicted as starting material arecommercially available. Reaction conditions are as described above inthe scheme; however, the skilled artisan will appreciate that certainmodifications in the reaction conditions and/or reagents used arepossible.

Starting with commercially available tert-butyl3-hydroxypiperidine-1-carboxylate, mesylation with methanesulfonylchloride in the presence of triethylamine in DCM provided mesylate 2.Displacement of the mesylate with pyrazole and NaH in DMF gaveintermediate 3. Removal of the Boc group with HCl (4 M in dioxane) inDCM gave the required piperidine 4.

Scheme 5 represents a general scheme for the preparation of2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepines, and2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepines used in theinvention. In Scheme 5, R₇ is —C₁₋₃ alkyl, halo, CN, —OC₁₋₃alkyl,—CH₂—O—CH₃, or OH; R₈ and R₉ are hydrogen, C₁₋₃alkyl, orC₃₋₆spirocycloalkyl. Substituted 2-bromobenzaldehyde or substituted2-fluorobenzaldehyde depicted as starting material are commerciallyavailable. Reaction conditions are as described above in the scheme;however, the skilled artisan will appreciate that certain modificationsin the reaction conditions and/or reagents used are possible.

Reductive amination of the starting aldehyde with the appropriateaminoalcohol followed by displacement of the bromide or fluoro providesthe required intermediate 3. This was then protected as the Boccarbamate to facilitate purification. It will be appreciated by theskilled artisan that alternative protecting groups may be used.Deprotection yields the requisite amine 5.

Scheme 6 represents a general scheme for the preparation of(R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepines, and2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepines used in theinvention. In Scheme 6, R₇ and R₈ are defined previously. Substituted2-hydroxybenzaldehyde depicted as starting material is commerciallyavailable. Reaction conditions are as described above in the scheme;however, the skilled artisan will appreciate that certain modificationsin the reaction conditions and/or reagents used are possible.

Reductive amination of aldehyde with the appropriate aminoalcoholfollowed by Mitsunobo reaction provides the required intermediate 3.This was then protected as the Boc carbamate to facilitate purification.It will be appreciated by the skilled artisan that alternativeprotecting groups may be used. Deprotection yields the requisite amine5.

Scheme 7 represents a general scheme for the preparation ofsubstituted-tetrahydrobenzo[f][1,4]oxazepines used in the invention. Inscheme 7, R₈ is as defined previously. In this, 2-hydroxybenzamidedepicted as starting material is commercially available. Reactionconditions are as described above in the scheme; however, the skilledartisan will appreciate that certain modifications in the reactionconditions and/or reagents used are possible.

Reaction of 2-hydroxybenzamide with the appropriate bromoacetate yieldsthe intermediate 3. Cyclization under basic conditions followed byreduction of the resulting imide with LAH yields the required amine 5.

Scheme 8 represents a general scheme for the preparation of2,3,4,5-tetrahydro-1H-benzo[c]azepines used in the invention. In Scheme8, R₇ and R₈ are as defined previously. The substituted2-(bromomethyl)benzonitrile depicted as starting material iscommercially available. Reaction conditions are as described above inthe scheme; however, the skilled artisan will appreciate that certainmodifications in the reaction conditions and/or reagents used arepossible.

Reaction of starting 2-(bromomethyl)benzonitrile with the enolatedgenerated from the appropriate ester 2 yields nitrile 3. Reduction ofthe nitrile and ester functions with LAH followed by protection of theamine group and conversion of the alcohol to the mesylate leaving groupaffords intermediate 6. Completion of the desired 7 is accomplished bycyclization under basic condition with CuI.

Scheme 9 represents a general scheme for the preparation of2,3,4,5-tetrahydro-1H-benzo[c]azepines used in the invention. In Scheme9, R₇ and R₈ are as defined previously. The substituted2-(bromomethyl)benzonitrile depicted as starting material arecommercially available. Reaction conditions are as described above inthe scheme; however, the skilled artisan will appreciate that certainmodifications in the reaction conditions and/or reagents used arepossible.

Reaction of starting 2-(bromomethyl)benzonitrile with the enolategenerated from the appropriate ester 2 yields nitrile 3. Reduction ofthe nitrile and ester functions with LAH. Alcohol was then convertedintermediate 5 with thionyl chloride. Displacement of the chlorideprovides the intermediate 6 It was then protected with Boc group andthen deprotection to give desired 7 as hydrochloride salt.

Scheme 10 represents a general scheme for the preparation oftetrahydropyrido[1,4]oxazepine hydrochloride used in the invention. InScheme 10, R₈ and R₉ are as defined previously. Thefluoronicotinaldehyde, chloronicotinaldehyde or bromonicotinaldehydedepicted as starting material are commercially available. Reactionconditions are as described above in the scheme; however, the skilledartisan will appreciate that certain modifications in the reactionconditions and/or reagents used are possible.

Reductive amination of the starting aldehyde with the appropriateaminoalcohol followed by displacement of the bromide or fluoro providesthe required intermediate 3. This was then protected as the Boccarbamate to facilitate purification. It will be appreciated by theskilled artisan that alternative protecting groups may be used.Deprotection yields the requisite amine 5 as hydrochloride salt.

Scheme 11 represents a general scheme for the preparation of(R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine hydrochloride,and 2,2-dimethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepinehydrochloride used in the invention. In Scheme 11, R₈ is as definedpreviously. The 3-hydroxypicolinaldehyde depicted as starting materialis commercially available. Reaction conditions are as described above inthe scheme; however, the skilled artisan will appreciate that certainmodifications in the reaction conditions and/or reagents used arepossible.

Reductive amination of the commercially available aldehyde with theappropriate aminoalcohol followed by Mitsunobo reaction provides therequired intermediate 3. This was then protected as the Boc carbamate tofacilitate purification. It will be appreciated by the skilled artisanthat alternative protecting groups may be used. Deprotection yields therequisite amine 5.

Scheme 12 represents a general scheme for the preparation of(R)-2-ethyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine used in theinvention. In this, 2-bromo-3-(bromomethyl)pyridine depicted as startingmaterial are commercially available. Reaction conditions are asdescribed above in the scheme; however, the skilled artisan willappreciate that certain modifications in the reaction conditions and/orreagents used are possible.

Treatment of commercially avialable 2-bromo-3-(bromomethyl)pyridine withammonium hydroxide yields primary amine 2. Alkylation via epoxideopening followed by displacement of the bromide provides intermediate 4.

Scheme 13 represents a general scheme for the preparation of2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride, and2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride usedin the invention. In Scheme 13, R₈ and R₉ are as defined previously. Thesubstituted 1-bromo-2-(bromomethyl)benzene depicted as starting materialare commercially available. Reaction conditions are as described abovein the scheme; however, the skilled artisan will appreciate that certainmodifications in the reaction conditions and/or reagents used arepossible.

Alkylation with the appropriate aminoalcohol followed by displacement ofthe bromide provides the required intermediate 3.

Scheme 14 represents a general scheme for the preparation of2,2,8-trimethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepinehydrochloride used in the invention. In this,4-hydroxy-6-methylnicotinic acid depicted as starting material iscommercially available. Reaction conditions are as described above inthe scheme; however, the skilled artisan will appreciate that certainmodifications in the reaction conditions and/or reagents used arepossible.

Commercially available acid 1 was converted to the acid chloride withPOCl₃, followed by amide formation to give intermediate 3. Reduction ofthe amide with borane dimethyl sulfide produces amine 4. Cyclizationwith potassium tert-butoxide as base followed by amine protection as thetert-butylcarbamate group yields compound 5. Deprotection under acidiccondition yields the requisite amine 6.

Scheme 15 represents a general scheme for the preparation of1-ethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine used in theinvention. In this, the 1-(bromomethyl)-2-nitrobenzene depicted asstarting material are commercially available. Reaction conditions are asdescribed above in the scheme; however, the skilled artisan willappreciate that certain modifications in the reaction conditions and/orreagents used are possible.

Reaction of starting 1-(bromomethyl)-2-nitrobenzene with 2-aminoacetateprovides intermediate 2. Boc protected the amine, followed by reductionof nitro to anilines to yield intermediate 4. Cyclization with HOBtyields intermediate 5, followed by alkylation. Deprotection under acidiccondition followed by reduction with LAH to provide desired intermediate7.

Scheme 16 represents a general scheme for the preparation of compoundsaccording to Formula (I). In Scheme 16 R₂ is as in Formula 1 and R₆ isC₁₋₃alkyl, halo, or —OC₁₋₃alkyl. R₁₀ is

—C₁₋₃ alkyl —C₄₋₇ cycloalkyl —C₅₋₇ heterocycloalkyl,—CH₂-azabicycloheptanyl, or —CH₂— azabicyclohexanyl. The carboxylic acid1 depicted as starting material is commercially available or may besynthesized from readily available materials. Reaction conditions are asdescribed above in the scheme; however, the skilled artisan willappreciate that certain modifications in the reaction conditions and/orreagents used are possible.

The commercially available carboxylic acid 1 was treated with sulfuricacid in methanol to produce methyl ester 2, which can be reduced byLiAlH₄ in THF and oxided with PCC in DCM to obtain the intermediatealdehyde 4. Compound 4 is treated with oxaldehyde and NH₄OH to affordthe desired imidazole 5. Alkylation of 5 by treating with intermediate 6under basic conditions followed by hydrolysis with NaOH in a suitablesolvent produces desired product 7.

Scheme 17 represents a general scheme for the preparation of compoundsaccording to Formula (I). In scheme 17, R₂ and R₅ are as definedpreviously. The triazole 1 depicted as starting material is commerciallyavailable. Reaction conditions are as described above in the scheme;however, the skilled artisan will appreciate that certain modificationsin the reaction conditions and/or reagents used are possible.

Commercially available 1H-1,2,3-triazole 1 is treated with(bromomethyl)cyclohexane in the presence of Cs₂CO₃ and NaI in DMF toafford intermediate 2. Completion of the synthesis is accomplished viareaction with 3 under basic conditions followed by hydrolysis with NaOHin a suitable solvent to produce 4.

Scheme 18 represents a general scheme for the preparation of compoundsaccording to Formula (I). In Scheme 18, R₂ and R_(e) are as definedpreviously. The carboxylic acid ester 1 depicted as starting material iscommercially available. Reaction conditions are as described above inthe scheme; however, the skilled artisan will appreciate that certainmodifications in the reaction conditions and/or reagents used arepossible.

The commercially available methyl ester 1 is treated with hydrazine inmethanol to obtain hydrazide compound 2. Reaction with ethanethioamideand pyrinde in 1-butanol produces triazole 3. Alkylation of intermediate3 with chloride 4 in the presence of NaH in DMF, followed by hydrolysiswith NaOH in a suitable solvent produces desired product 5.

Scheme 19 represents a general scheme for the preparation of compoundsaccording to Formula (I). In Scheme 19, R₂ and Re are as definedpreviously. The alcohol 1 depicted as starting material is commerciallyavailable or may be synthesized from readily available materials.Reaction conditions are as described above in the scheme; however, theskilled artisan will appreciate that certain modifications in thereaction conditions and/or reagents used are possible.

Alcohol 1 is converted to acid 4 in a 3 step sequence involvingconverstion to the chloride with SOCl₂ in DCM first, followed bytreating with KCN in a mixture of ethanol and water to produce thenitrile 3 and hydrolysis of nitrile 3 with NaOH in ethanol. Compound 4is treated with oxalyl chloride followed by cyclohexylmethanamine andEt₃N to produce intermediate 5. Tetrazole 6 is formed by treating 5 withPCl₅ and TMSN₃ in toluene. Conversion of the bromide to the boronate 7was accomplished by treating with diboron in presence of PdCl₂ (dppf)and KOAc in 1,4-dioxane. The synthesis can be completed by rhodiumcatalyzed Michael addition of 7 with intermediate 8 followed byhydrolysis with NaOH in suitable solvents.

Scheme 20 represents a general scheme for the preparation of compoundsaccording to Formula (I). In Scheme 20, R₂ and R₆ are as definedpreviously. The aldehyde 1 depicted as starting material is commerciallyavailable or may be synthesized from readily available materials.Reaction conditions are as described above in the scheme; however, theskilled artisan will appreciate that certain modifications in thereaction conditions and/or reagents used are possible.

The commercially available aldehyde 1 is treated with TOSMIC and NH₃ inmethanol to provide intermediate 2. Alkylation of intermediate 2 withintermediate 3 in presence of NaH in DMF, followed by hydrolysis in NaOHand suitable solvents to produce desired product 4.

Scheme 21 represents a general scheme for the preparation of compoundsaccording to Formula (I). In Scheme 21, R₁₄ is C₁₋₃alkyl or Benzyl, R₅is C₁₋₃alkyl or —(CH₂)₂—O—(CH₂)₂—OR₄ (as defined in Formula 1), R₂ andR₆, are as defined previously. The triazole 1 depicted as startingmaterial may be synthesized from readily available materials. Reactionconditions are as described above in the scheme; however, the skilledartisan will appreciate that certain modifications in the reactionconditions and/or reagents used are possible.

Treatment of triazole 1 with ethyl acrylate or benzyl acrylate in thepresence of palladium (II) acetate and diisopropylethyl amine in thepresence of a suitable solvent produces the desired Heck cross-couplingproduct 2. It will appreciated by the skilled artisan that otheracrylates may be used for the Heck cross-coupling and that compound 2may also be obtained via a Wittig olefination reaction starting from theappropriate aldehyde of compound 1. Further transformation of the olefin2 can be achieved through rhodium mediated cross-coupling of theappropriate boronic acid or boronic ester 3 in the presence oftriethylamine. It will be recognized by the skilled artisan that theconditions for this Rh catalyzed Michael reaction may be modified by theappropriate selection of ligands, Rh source, solvent and temperature inorder to achieve enantioselectivity wherein the chirality at the carbon1 to the carboxylate may favor one or the other of the possibleenantiomers. Benzylic alcohol 4 can be transformed to the requisitechloride 5 using thionyl chloride.

Scheme 22 shows a general scheme for the preparation of6-chloro-3,7-dimethyl-3H-[1,2,3]triazolo[4,5-c]pyridine. Starting withcommercially available 2-chloro-5-fluoro-3-methylpyridine, oxidationprovides intermediate 2. This is subsequently converted to nitrointermediate 3. Displacement of the fluoride using an appropriate aminefollowed by nickel metal reduction of the nitro to the aniline, yields4. Diazotization and cyclization provides the required triazole 5.

Scheme 23 represents a general scheme for the preparation of compoundsaccording to Formula (I). In Scheme 23, R₂ and R₆ are as definedpreviously. R₁₁ is methyl or cyclopropyl and R₁₂ is CH₂-A where A is asdefined in Formula (I). The triazole 1 depicted as starting material maybe synthesized from readily available materials. Reaction conditions areas described above in the scheme; however, the skilled artisan willappreciate that certain modifications in the reaction conditions and/orreagents used are possible.

Treatment of triazole 1 with ethyl acrylate in the presence of palladium(II) acetate and diisopropylethyl amine in the presence of a suitablesolvent produces the desired Heck cross-coupling product 2. It willappreciated by the skilled artisan that other acrylates may be used forthe Heck cross-coupling and that compound 2 may also be obtained via aWittig olefination reaction starting from the appropriate aldehyde ofcompound 1. Further transformation of the olefin 2 can be achievedthrough rhodium mediated cross-coupling of the appropriate boronic acidor boronic ester 3 in the presence of triethylamine. Benzylic alcohol 4can be transformed to the requisite chloride 5 using thionyl chloride.Completion of the desired acid 6 is accomplished in a two step sequenceinvolving reaction of the chloride with the requisite amine, andconversion of the ester to the acid.

Scheme 24 represents a general scheme for the preparation of compoundsaccording to Formula (I). In Scheme 24, R₂, R₆, and A are as definedpreviously. The triazole 1 depicted as starting material may besynthesized from readily available materials. Reaction conditions are asdescribed above in the scheme; however, the skilled artisan willappreciate that certain modifications in the reaction conditions and/orreagents used are possible.

Treatment of triazole 1 with ethyl acrylate in the presence of palladium(II) acetate and diisopropylethyl amine in the presence of a suitablesolvent produces the desired Heck cross-coupling product 2. It willappreciated by the skilled artisan that other acrylates may be used forthe Heck cross-coupling and that compound 2 may also be obtained via aWittig olefination reaction starting from the appropriate aldehyde ofcompound 1. Further transformation of the olefin 2 can be achievedthrough rhodium mediated cross-coupling of the appropriate boronic acidor boronic ester 3 in the presence of triethylamine. Benzylic alcohol 4can be transformed to the requisite chloride 5 using thionyl chloride.Completion of the desired acid 6 is accomplished in a two step sequenceinvolving reaction of the chloride with the requisite amine, andconversion of the ester to the acid.

Scheme 25 represents a general scheme for the preparation of compoundsaccording to Formula (I). In Scheme 25, R₂, R₅, R₆, R₁₁, R₁₂, R₁₄ and Aare as defined previously. The starting material 1 can be synthesizedfrom readily available materials. Reaction conditions are as describedabove in the scheme; however, the skilled artisan will appreciate thatcertain modifications in the reaction conditions and/or reagents usedare possible.

Treatment of 1 with t-butyldimethylsilyl chloride and imidazole providesthe silyl ether 2. Enolate formation with lithium diisopropylamide andreaction with methyl iodide gives alpha methylated product 3. Reactionwith tetrabutylammonium fluoride furnishes benzylic alcohol 4 which canbe converted to the chloride with thionyl chloride. The synthesis can becompleted as previously described via reaction with the appropriateamine followed by conversion of the ester to the acid.

Scheme 26 represents a general scheme for the preparation of compoundsaccording to Formula (I). In Scheme 26, R₂, R₅, R₆, R₁₁, R₁₂, R₁₄ and Aare as defined previously. The starting material 1 can be synthesizedfrom readily available materials. Reaction conditions are as describedabove in the scheme; however, the skilled artisan will appreciate thatcertain modifications in the reaction conditions and/or reagents usedare possible.

Treatment of 1 with t-butyldimethylsilyl chloride and imidazole providesthe silyl ether 2. Conversion of the ester to the acid can beaccomplished either via hydrolysis under basic conditions such as NaOHand water with a suitable co-solvent or in the case where R9 is a benzylgroup via hydrogenation with 10% Pd—C to furnishes acid 3. Treatmentwith carbonyl diimidazole in tetrahydrofuran followed by reaction with1,8-Diazabicyclo[5.4.0]undec-7-ene and (S)-4-benzyloxazolidin-2-oneprovides 4. Enolate formation with sodium bis(trimethylsilyl)amide andstereoselective trapping with methyl iodide gives 5. Removal of thet-butyldimethylsilyl ether with tetrabutylammonium fluoride furnishesbenzylic alcohol 6, which is converted to the requisite chloride withthionyl chloride. The synthesis can be completed as previously describedvia reaction with the appropriate amine followed by conversion of theester to the acid.

Scheme 27 represents a general scheme for the preparation of compoundsaccording to formula I. In Scheme 27, R₂, R₅ and R₁₄ are as definedpreviously. R₁₃ is A or A-linker as in Formula (I). The acetylenic alkylalcohols 1 depicted are commercially available. Reaction conditions areas described above in the scheme; however, the skilled artisan willappreciate that certain modifications in the reaction conditions and/orreagents used are possible.

Aldehyde 2 is best obtained from the alcohols 1 by Swern oxidation.Other well known methods for oxidation of alkyl alcohols to aldehydes,such as pyridinium chlorochromate oxidation or use of the Dess Martinreagent may also be applied. It will be appreciated by the skilledartisan that compound 3 may be obtained by either the Horner WadsworthEmmons reaction or a Wittig olefination reaction starting from theappropriate aldehyde 2 and the stabilized phophonium ylide as shown inthe scheme or the unstabilized ylide. The triazines 4 are prepared bystandard click conditions either using commercially availableorgano-azides, Cu(II), and a suitable reducing agent such as sodiumascorbate to generate the Cu(I) catalyst or alternatively by in situformation of an alkyl azide by reaction of an alkyl halide with sodiumazide followed by reaction in the presence of a commercially availablesource of Cu(I) such as CuI. Further transformation of the olefin 4 canbe achieved through rhodium mediated cross-coupling of the appropriateboronic acid or boronic ester in the presence of triethylamine to affordthe methylphenyl alcohol 5. It will also be recognized by the skilledartisan that the conditions for this Rh catalyzed Michael reaction maybe modified by the appropriate selection of ligands, Rh source, solventand temperature in order to achieve enantioselectivity wherein thechirality at the carbon 1 to the carboxylate may favor one or the otherof the possible enantiomers. Completion of the analog synthesis isaccomplished via conversion of the alcohol to the chloride or bromide.It will appreciated by the skilled artisan that the benzylic alcohol 5may be converted to an alternative leaving group such as, but notlimited to, mesylate, tosylate, or iodide. Reaction of intermediate 6with R₁₃H followed by conversion of the ester in the presence ofsuitable co-solvents to assure adequate solubility of the reactantsaffords the final target carboxylic acids 7.

Scheme 28 depicts a method for further elaboration of the obtainedcompounds by alkylation a to the carboxylate. In Scheme 28, R₂, R₅ R₁₃and R₁₄ are as defined previously. As is well known in the chemicalliterature ester enolate alkylation requires formation of the kineticenolate with relatively strong, nonnucleophillic bases such as lithiumdiisopropyl amide or lithium bis-silyl amide at low temperature in orderto prevent self reaction of the enolate with starting ester. However, inorder to control the reaction at other acidic centers the base must becarefully selected to have just enough bascicity to effect thedeprotonation of methylene alpha to the ester while avoiding otheracidic centers within the molecule. Alkylation of the dianion where R₅═Hfor acids can also be achieved. For cases where the substate is anester, appropriate choice of ester may be advantageous after alkylationbecause of the potential for steric hinderence of normal aqueoushydrolysis upon addition of the alkylating agent exemplified by MeI.

In Scheme 29, R₂, R₅ and R₁₃ are as previously defined. R₁₀₁ is aprotecting group linked to an oxygen; for exampledimethy-tert-butyl-silyl or para-methoxy benzyl. Similar to the esterhydrolysis there may be a steric influence on the addition of a secondalkylating agent to the ester and an alternative route could be achievedas depicted in Scheme 29. By this method the aryl halide exemplified by13 is metallated by halogen metal exchange with a suitableorganometallic such as alkyl lithium or alkyl magnesium. Alternatively,the use of lithium trialkyl magnesium ate complexes (for examplei-PrBu₂MgLi) have been effective for halogen metal exchange for somesubstrates. Additionally certain Grignard reagents complexed with oneequivalent of LiCl have been identified by some as so-called“turbogrignard reagents” for their useful reactivity in halogen-metalexchange reactions as well as compatibility in these reactions withfunctional groups having reactivity towards organolithium reagents.These “turbogrignard” reagents might also be useful for the halogenmetal exchange in certain cases. Some of these reagents, such asi-PrMgCl*LiCl are commercially available. Upon generation of the arylmetal reagent the addition of acetylenic aldehyde 14 will afford thesecondary benzylic alcohol 15. Conversion of the alcohol to the benzylicbromide 16 as might then be mildly achieved with CBr₄ and triphenylphosphine as well as other methods such as PBr₃ to afford a somewhatreactive electrophillic substrate. Reaction of 16 with enolates such asthat derived from iso-butyates as depicted in the Scheme 29 affords thesterically hindered esters 17. The use of an additive such as1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) may improvethe effectivness of this reaction. The resulting dialkylated ester 17containing the TMS protected acetylene can be de-silylated with aqueouscarbonate and subjected to click reaction as described above to affordthe triazoles such as 18 followed by removal of the hydroxyl protectinggroup and then activation of the benzylic alcohol to a benzylic chlorideand subsequent displacement of the chloride with a suitable electrophilesuch as a secondary amine or a sulfonamide to afford 19. Alternativelythe benzylic alcohol may also be displaced by a suitably acidicnucleophile such as a sulfonamide to afford 19 under Mitsunobuconditions. The ester in 19 is then removed by methods which aresuitable for ester cleavage of a highly sterically hindered ester suchas 19, affording the carboxylic acid product 20. Furthermore, in somecases it may be advantageous to prepare the α-carboxy monoalkylatedcompounds by this same route replacing the butyrate with a propionate.One possible advantage of doing this is that by using an appropriatelychosen chiral auxilary to replace the ester it may be possible to effectdiastereoselective additions to the bromide allowing for synthesis ofthe preferred stereoisomers.

Scheme 30 represents a general scheme for the preparation of compoundsaccording to Formula (I). In Scheme 30, R₂, R₆ and A are as definedpreviously. Triazole 1 is either commercially available or may besynthesized from readily available materials. Reaction conditions are asdescribed above in the scheme; however, the skilled artisan willappreciate that certain modifications in the reaction conditions and/orreagents used are possible.

Treatment of triazole 1 with n-butyl lithium and DMF in presence of asuitable solvent produces the desired aldehyde product 2. The couplingpartner for aldehyde 2 is obtained by first protecting the benzylicalcohol 3 as its para-methoxybenzylether. It will be appreciated thatalternative protecting groups are possible. Coupling of the aldehyde 2and bromide 4 can be accomplished via treatment of the bromide firstwith t-butyl lithium or n-butyl lithium followed by addition of thealdehyde. However, the skilled artisan will appreciate that otheraldehydes, such as substituted phenyl aldehyde may also be applied.Intermediate alcohol 6, arises from treatment of alcohol 5 with theappropriate silylketene acetal in the presence of a Lewis acid or viaone-pot brϕnsted base/brϕnsted acid system, followed by deprotectionwith DDQ. Benzylic alcohol 6 can be transformed to the requisitechloride 7 using thionyl chloride. Completion of the synthesis can beaccomplished by deplacement of chloride, following by hydrolysis of theester to produce 8

It will be also be appreciated by the skilled artisan that intermediate5 may be prepared by coupling bromide 1 with aldehyde 9.

Scheme 31 represents a general scheme for the preparation of2-ethyl-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine used in theinvention. In Scheme 31, substituted 2-bromobenzaldehyde depicted asstarting material is commercially available. Reaction conditions are asdescribed above in the scheme; however, the skilled artisan willappreciate that certain modifications in the reaction conditions and/orreagents used are possible.

Reductive amination of aldehyde 1 with the appropriate aminoalcoholfollowed by alkylation reaction provides the required intermediate 3.

Scheme 32 represents a general scheme for the preparation of1-((1H-imidazol-2-yl)methyl)azepane used in the invention. Substituted1-azepan-2-one depicted as starting material is commercially available.Reaction conditions are as described above in the scheme; however, theskilled artisan will appreciate that certain modifications in thereaction conditions and/or reagents used are possible.

Reducing the amide with the appropriate reducing reagent followed by areductive amination reaction provides the required intermediate 3.

Scheme 33 represents a general scheme for the preparation of1-((1H-imidazol-2-yl)methyl)-4-ethylpiperidine used in the invention.Substituted 1-tert-butyl 4-ethylpiperidine-1-carboxylate depicted asstarting material is commercially available. Reaction conditions are asdescribed above in the scheme; however, the skilled artisan willappreciate that certain modifications in the reaction conditions and/orreagents used are possible.

Deprotection under acidic conditions followed by a reductive aminationreaction provides the required intermediate 3.

Scheme 34 represents a general scheme for the preparation of compoundsaccording to Formula (I). In Scheme 34, R₂, R₅ and R₆ are as definedpreviously. The cycloheptylmethanol 1 depicted as starting material iscommercially available. Reaction conditions are as described above inthe scheme; however, the skilled artisan will appreciate that certainmodifications in the reaction conditions and/or reagents used arepossible.

Commercially available cycloheptylmethanol 1 is treated with TsCl in thepresence of Et₃N in DCM to afford intermediate 2 followed by reductiveamination reaction provides the required intermediate 3. Completion ofthe synthesis is accomplished via reaction with 4 under basic conditionsfollowed by hydrolysis with LiOH in a suitable solvent to produce 5.

Scheme 35 represents a general scheme for the preparation of4,5-dihydro-3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclopropane] used inthe invention. In this, the (bis-tert-butoxycarbonyl)amine depicted asstarting material are commercially available. Reaction conditions are asdescribed above in the scheme; however, the skilled artisan willappreciate that certain modifications in the reaction conditions and/orreagents used are possible.

Reaction of starting (bis-tert-butoxycarbonyl)amine with1-(benzyloxy)-2-(chloromethyl)benzene provides intermediate 2.Deprotection of the phenol by hydrogenation, followed by reacting with2,4-dibromobutanoate under basic conditions to yield intermediate 4.Treatment of intermediate 4 with potassium tert-butoxide is to yieldintermediate 5. Deprotection under acidic conditions followed bycyclolization and reduction with LAH provides desired intermediate 8.

Scheme 36 represents a general scheme for the preparation of4,5-dihydro-3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclobutane] used inthe invention. In this, the 2-hydroxybenzaldehyde depicted as startingmaterial are commercially available. Reaction conditions are asdescribed above in the scheme; however, the skilled artisan willappreciate that certain modifications in the reaction conditions and/orreagents used are possible.

Reaction of starting 2-hydroxybenzaldehyde 1 with1-bromocyclobutanecarboxylate provides intermediate 2, followed byreduction of aldehyde to hydroxy amine to yield intermediate 4.Cyclolization with DIPEA to yield intermediate 5, followed by reductionwith LAH to provide desired intermediate 6.

Scheme 37 represents a general scheme for the preparation of2-(oxepan-4-ylmethyl)-1H-imidazole used in the invention. In this, the2-(oxepan-4-yl)ethanol depicted as starting material are commerciallyavailable. Reaction conditions are as described above in the scheme;however, the skilled artisan will appreciate that certain modificationsin the reaction conditions and/or reagents used are possible.

The commercially available 2-(oxepan-4-yl)ethanol 1 is treated with PCCin DCM to produce aldehyde 2, which can be reacted with oxalaldehyde,and ammonia hydrate to produce intermediate 3.

Scheme 38 represents a general scheme for the preparation of7-cyclopropyl-2-ethyl-1,4-oxazepane used in the invention. In this, the3-aminopropanoic acid depicted as starting material is commerciallyavailable. Reaction conditions are as described above in the scheme;however, the skilled artisan will appreciate that certain modificationsin the reaction conditions and/or reagents used are possible.

Protection of 3-aminopropanoic acid 1 with TsCl is followed by formingN-Methoxy-N-methyl intermediate 3. Then it is treated withcyclopropylmagnesium bromide to provide intermediate 4, followed byreduction with NaBH₄ to yield alcohol 5. Intermediate 5 is treated with1-bromobutan-2-one under basic condition to yield intermediate 6,followed by cyclolization and depretection to yield intermediate 8.After, it is protected with BOC, followed by deprotection to yieldintermediate 10.

Scheme 39 represents a general scheme for the preparation of compoundsaccording to Formula (I). In Scheme 39, R₂, R₆, R₁₃, and A are asdefined previously. Alcohol 1 is synthesized according to scheme 30.Reaction conditions are as described above in the scheme; however, theskilled artisan will appreciate that certain modifications in thereaction conditions and/or reagents used are possible.

Treatment of alcohol 1 with thionyl chloride in DCM gives the chlorideintermediate 2. Reformatsky reaction with Zn yields the ester 3.Deprotection of PMB group with DDQ followed by treatment with thionylchloride produces intermediate 4. Completion of the synthesis can beaccomplished by displacement of the chloride, following by hydrolysis ofthe ester to produce 5

Scheme 40 represents a general scheme for the preparation of compoundsaccording to Formula (I). In Scheme 40, R₁₃ and A are as definedpreviously. Methyl 3-methylpicolinate 1 is commercially available.Reaction conditions are as described above in the scheme; however, theskilled artisan will appreciate that certain modifications in thereaction conditions and/or reagents used are possible.

Treatment of Methyl 3-methylpicolinate 1 with m-CPBA in DCM produces thedesired pyridine oxide 2. Bromination of 2 with phosphoryl tribromideproduces intermediate bromide 3. Reduction of 3 with LAH, followed byprotection of the alcohol as the TBS ether yields intermediate 4.Coupling of the aldehyde 5 and bromide 4 can be accomplished viatreatment of the bromide first with n-butyl lithium followed by additionof the aldehyde. Intermediate benzyl alcohol 7, arises from treatment ofalcohol 6 with the appropriate silylketene acetal in the presence of aLewis acid or via one-pot Br nsted base/Br nsted acid system, followedby deprotection with TBAF. Benzylic alcohol 7 can be transformed to therequisite chloride 8 using thionyl chloride. Completion of the synthesiscan be accomplished by displacement of the chloride, followed byhydrolysis of the ester to produce 9.

Scheme 41 represents a general scheme for the preparation of compoundsaccording to Formula (I). Ethyl 5-bromo-2-methylnicotinate 1 iscommercially available. In Scheme 41, R₁₃ and A are as definedpreviously. Reaction conditions are as described above in the scheme;however, the skilled artisan will appreciate that certain modificationsin the reaction conditions and/or reagents used are possible.

Reduction of ethyl 5-bromo-2-methylnicotinate 1 accomplished with LAH.The resulting alcohol was protected as the TBS ether to yieldintermediate 3. Coupling of the aldehyde 4 and bromide 3 can beaccomplished via treatment of the bromide first with n-butyl lithiumfollowed by addition of the aldehyde. Intermediate benzyl alcohol 6,arises from treatment of alcohol 5 with the appropriate silylketeneacetal in the presence of a Lewis acid or via one-pot Br nsted base/Brnsted acid system, followed by deprotection with TBAF. Benzylic alcohol6 can be transformed to the requisite chloride 7 using thionyl chloride.Completion of the synthesis can be accomplished by displacement of thechloride, followed by hydrolysis of the ester to produce 8

Scheme 42 represents a general scheme for the preparation of3-((1H-Pyrazol-1-yl)methyl)piperidine 4 used in the invention.Tert-Butyl 3-(bromomethyl)piperidine-1-carboxylate 1 is commerciallyavailable. Reaction conditions are as described above in the scheme;however, the skilled artisan will appreciate that certain modificationsin the reaction conditions and/or reagents used are possible.

Starting with the bromide 1, displacement of the bromide with pyrazole 2in the presence of NaH gives Boc protected intermediate 3. Removal ofthe Boc group under acidic conditions yields product 4.

Scheme 43 represents a general scheme for the preparation of compoundsaccording to Formula (I). In Scheme 43, R₂, R₅, R₆, and R₁₄ are asdefined previously. Ester 1 is synthesized according to Scheme 30.Reaction conditions are as described above in the scheme; however, theskilled artisan will appreciate that certain modifications in thereaction conditions and/or reagents used are possible.

Ester 1 was separated by Chiral SFC to give a single enantiomericallypure product 2 and a single enantiomerically pure product 3.

Scheme 44 represents a general scheme for the preparation of(R)-2-Ethyl-9-fluoro-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine,hydrochloride used in the invention. The4-chloro-5-fluoronicotinaldehyde as starting material is commerciallyavailable. Reaction conditions are as described above in the scheme;however, the skilled artisan will appreciate that certain modificationsin the reaction conditions and/or reagents used are possible.

Commercially available (R)-2-ethyloxirane 1 was opened with ammoniumhydroxide to obtain (R)-1-aminobutan-2-ol 2. Reductive amination of thecommercially available aldehyde 3 with (R)-1-aminobutan-2-ol 2 followedby displacement of the chloride provides the required intermediate 5.This was then protected as the Boc carbamate to facilitate purification.It will be appreciated by the skilled artisan that alternativeprotecting groups may be used. Deprotection yields the requisite amine7.

Scheme 45 represents a general scheme for the preparation of(R)-2-Ethyl-6-fluoro-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine and(R)-6-Bromo-2-ethyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine usedin the invention. The 4-bromo-2-fluoronicotinaldehyde as startingmaterial is commercially available. Reaction conditions are as describedabove in the scheme; however, the skilled artisan will appreciate thatcertain modifications in the reaction conditions and/or reagents usedare possible.

Commercially available (R)-2-ethyloxirane 1 was opened with ammoniumhydroxide to obtain enantiomerically pure (R)-1-aminobutan-2-ol 2.Reductive amination of the commercially available aldehyde 3 with(R)-1-aminobutan-2-ol 2 followed by displacement of the halogen givesamine 5 and amine 6.

Scheme 46 represents a general scheme for the preparation of(R)-8-Chloro-2-ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepinehydrochloride used in the invention. The(4,6-dichloropyridin-3-yl)methanol as starting material is commerciallyavailable. Reaction conditions are as described above in the scheme;however, the skilled artisan will appreciate that certain modificationsin the reaction conditions and/or reagents used are possible.

Commercially available (R)-2-ethyloxirane 1 was opened with ammoniumhydroxide to obtain (R)-1-aminobutan-2-ol 2. Bromination of alcohol 3with PBr₃ in DCM produces intermediate 4. Alkylation of 4 with(R)-1-aminobutan-2-ol 2 followed by displacement of the chlorideprovides the required intermediate 6. This was then protected as the Boccarbamate to facilitate purification. It will be appreciated by theskilled artisan that alternative protecting groups may be used.Deprotection yields the requisite amine 8.

Scheme 47 represents a general scheme for the preparation of triazole 5used in the invention. In Scheme xx, R₅ and R₆ are defined previously.Substituted 1-fluoro-2-nitrobenzene depicted as starting material iscommercially available. Reaction conditions are as described above inthe scheme; however, the skilled artisan will appreciate that certainmodifications in the reaction conditions and/or reagents used arepossible.

Starting with commercially available substituted 1-fluoro-2-nitrobenzene1, dbbisplacement of the fluoride using an appropriate amine followed bybromination with NBS provides intermediate 3. Reduction of the nitrousing Raney nickel in water provides the aniline 4. Diazotization andcyclization provides the required triazole 5. Completion of the fullyelaborated analog can be accomplished in a fashion analogous to thatshown in scheme 23.

Scheme 48 represents a general scheme for the preparation of compoundsaccording to Formula (I). In Scheme 48, R₂, R₅, R₆, R₁₄, A and Z are asdefined previously. The starting material 1 can be synthesized fromreadily available materials. Reaction conditions are as described abovein the scheme; however, the skilled artisan will appreciate that certainmodifications in the reaction conditions and/or reagents used arepossible.

Treatment of 1 with t-butyldimethylsilyl chloride and imidazole providesthe silyl ether 2. Conversion of the ester to the acid can beaccomplished either via hydrolysis under basic conditions such as NaOHand water with a suitable co-solvent or in the case where R₁₄ is abenzyl group via hydrogenation with 10% Pd—C to furnish acid 3.Treatment with carbonyl diimidazole in tetrahydrofuran followed byreaction with 1,8-Diazabicyclo[5.4.0]undec-7-ene and(R)-4-benzyloxazolidin-2-one provides 4. Enolate formation with sodiumbis(trimethylsilyl)amide and stereoselective trapping with methyl iodidegives 5. Removal of the t-butyldimethylsilyl ether with HCl furnishesbenzylic alcohol 6, which is converted to the requisite chloride withthionyl chloride. The synthesis can be completed as previously describedvia reaction with the appropriate amine followed by conversion of theester to the acid 8.

Scheme 49 represents a general scheme for the preparation of acylsulfonamide 3 used in the invention. The starting material 1 can besynthesized from readily available materials. Reaction conditions are asdescribed above in the scheme; however, the skilled artisan willappreciate that certain modifications in the reaction conditions and/orreagents used are possible.

Conversion of the ester 1 to the acid 2 can be accomplished viahydrolysis under basic conditions such as LiOH and water with a suitableco-solvent. The synthesis can be completed by the coupling of acid 2with methanesulfonamide in the presence of EDC and DMAP to give 3. Itwill be appreciated by the skilled artisan that alternative couplingreagents may be used.

Scheme 50 represents a general scheme for the preparation of compoundsaccording to Formula (I). In Scheme 50, R₂, R₅, R₆ and A are as definedpreviously. Triazole 1 is either commercially available or may besynthesized from readily available materials. Reaction conditions are asdescribed above in the scheme; however, the skilled artisan willappreciate that certain modifications in the reaction conditions and/orreagents used are possible.

Treatment of triazole 1 with n-butyl lithium and DMF in presence of asuitable solvent produces the desired aldehyde product 2. The couplingpartner for aldehyde 2 is obtained by first protecting the benzylicalcohol 3 as its para-methoxybenzylether. It will be appreciated thatalternative protecting groups are possible. Coupling of the aldehyde 2and bromide 4 can be accomplished via treatment of the bromide firstwith t-butyl lithium or n-butyl lithium followed by addition of thealdehyde. However, the skilled artisan will appreciate that otheraldehydes, such as substituted phenyl aldehyde may also be applied.Intermediate benzyl alcohol 6, arises from treatment of alcohol 5 withthe appropriate silylketene acetal in the presence of a Lewis acid orvia one-pot Br nsted base/Br nsted acid system, followed by deprotectionwith DDQ. Benzylic alcohol 6 was separated by Chiral SFC to give asingle enantiomerically pure product 7. Alcohol 7 can be transformed tothe requisite chloride 8 using thionyl chloride. Completion of thesynthesis can be accomplished by deplacement of chloride, following byhydrolysis of the ester to produce 9

It will be also be appreciated by the skilled artisan that intermediate5 may be prepared by coupling bromide 1 with aldehyde 10.

Scheme 51 represents a general scheme for the preparation of acid 2 usedin the invention. The starting material 1 can be synthesized fromreadily available materials. Reaction conditions are as described abovein the scheme; however, the skilled artisan will appreciate that certainmodifications in the reaction conditions and/or reagents used arepossible.

Hydrolysis of the ester 1 using LiOH and peroxide then quenching withHCl produces acid 2.

Scheme 52 represents a general scheme for the preparation of 3-sulfonesubstituted-1-piperidine used in the invention. In this, the preparationof tert-butyl 3-mesylpiperidine-1-carboxylate depicted as startingmaterial was described before. Reaction conditions are as describedabove in the scheme; however, the skilled artisan will appreciate thatcertain modifications in the reaction conditions and/or reagents usedare possible.

Starting tert-butyl 3-mesylpiperidine-1-carboxylate 1 was treated withthiol under NaH condition to afford intermediate sulfide 2. Futheroxidation of sulfide into sulfone followed by deprotection oftert-butylcarboxylate group gave the required piperidine 3.

Biological Activity

As stated above, the compounds according to Formula I are NRF2regulators, and are useful in the treatment or prevention of humandiseases that exhibit oxidative stress components such as respiratoryand non-respiratory disorders, including COPD, asthma, fibrosis, chronicasthma and acute asthma, lung disease secondary to environmentalexposures, acute lung infection, chronic lung infection, al antitrypsindisease, cystic fibrosis, autoimmune diseases, diabetic nephropathy,chronic kidney disease, sepsis-induced acute kidney injury, acute kidneyinjury (AKI), kidney disease or malfunction seen during kidneytransplantation, Pulmonary Arterial Hypertension, atherosclerosis,hypertension, heart failure, Parkinson's disease (PD), Alzheimer'sdisease (AD), Friedreich's Ataxia (FA), amyotrophic lateral sclerosis(ALS), multiple sclerosis (MS), inflammatory bowel disease, coloncancer, neovascular (dry) AMD and neovascular (wet) AMD, eye injury,Fuchs Endothelial Corneal Dystrophy (FECD), uveitis or otherinflammatory eye conditions, Non-alcoholic Steatohepatitis (NASH),toxin-induced liver disease (e.g., acetaminophen-induced hepaticdisease), viral hepatitis, cirrhosis, psoriasis, dermatitis/topicaleffects of radiation, immunosuppression due to radiation exposure,Preeclampsia, and high altitude sickness.

The biological activity of the compounds according to Formula I can bedetermined using any suitable assay for determining the activity of acandidate compound as a NRF2 antagonist, as well as tissue and in vivomodels.

The biological activity of the compounds of Formula (I) are demonstratedby the following tests.

BEAS-2B NQO1 MTT Assay

NAD(P)H:quinone oxidoreductase 1 (NQO1), also called DT diaphorase, is ahomodimeric FAD-containing enzyme that catalyzes obligatoryNAD(P)H-dependent two-electron reductions of quinones and protects cellsagainst the toxic and neoplastic effects of free radicals and reactiveoxygen species arising from one-electron reductions. The transcriptionof NQO1 is finely regulated by NRF2, and thus NQO1 activity is a goodmarker for NRF2 activation. On day one, frozen BEAS-2B cells (ATCC) arethawed in a water bath, counted, and re-suspended at a concentration of250,000 cells/mL. Fifty microliters of cells are plated in 384 wellblack clear-bottomed plates. Plates are incubated at 37° C., 5% CO₂overnight. On day two, plates are centrifuged and 50 nL of compound orcontrols are added to the cells. Plates are then incubated at 37° C., 5%CO₂ for 48 hours. On day four, medium is aspirated from the plate andcrude cell lysates are made by adding 13 uL of 1× Cell SignalingTechnologies lysis buffer with 1 Complete, Mini, EDTA-free ProteaseInhibitor Tablet (Roche) for each 10 mL of lysis buffer. After lysisplates are incubated for 20 minutes at room temperature. Two microlitersof lysate are removed for use in Cell Titer Glo assay (Promega) and MTTcocktail is prepared (Prochaska et. al. 1998) for measurement of NQO1activity. Fifty microliters of MTT cocktail is added to each well, plateis centrifuged, and analyzed on an Envision plate reader (Perkin Elmer)using Absorbance 570 nm label for 30 minutes. Product formation ismeasured kinetically and the EC₅₀ of NQO1 specific activity induction iscalculated by plotting the change in absorbance (Delta OD/min) versusthe log of compound concentration followed by 3-parameter fitting.

All examples described herein possessed NQO1 specific enzyme activity inBEAS-2B cells with EC₅₀s between >10 uM-<lnM unless otherwise noted (seetable below). EC₅₀s

<1 nM (+++++), EC₅₀s 10 nM-1 nM (++++), EC₅₀s 10-100 nM (+++), EC₅₀s 100nM-1 uM (++), EC₅₀s 1-10 uM (+), EC₅₀s >10 uM (−), or were notdetermined (ND). Ex # EC50 Ex # EC50 Ex # EC50 Ex # EC50 Ex # EC50 1 +30 ++++ 59 +++ 88 ++ 117 + 2 ++ 31 +++++ 60 +++ 89 +++ 118 + 3 + 32 ++++61 +++ 90 +++ 119 +++ 4 + 33 +++ 62 +++ 91 ++ 120 ++++ 5 +++ 34 ++ 63+++ 92 + 121 +++++ 6 ++ 35 ++++ 64 +++ 93 ++++ 122 +++ 7 + 36 ++++ 65+++ 94 ++++ 123 +++ 8 ++++ 37 + 66 +++ 95 ++ 124 +++ 9 + 38 +++ 67 +++96 ++ 125 ++ 10 + 39 +++ 68 +++ 97 ++ 126 ++++ 11 + 40 +++ 69 +++ 98 ++127 +++ 12 ++ 41 ++ 70 +++ 99 + 128 + 13 + 42 ++ 71 ++ 100 +++ 129 ++14 + 43 + 72 + 101 +++++ 130 ++ 15 + 44 +++ 73 ++ 102 +++++ 131 ++ 16 +45 ++ 74 ++ 103 +++++ 132 + 17 + 46 ++ 75 ++ 104 ++++ 133 ++ 18 + 47 ++76 ++ 105 +++ 134 ++ 19 + 48 ++ 77 + 106 ++ 135 +++ 20 ++ 49 ++ 78 + 107+++ 136 +++ 21 + 50 +++ 79 + 108 + 137 ++ 22 ++++ 51 ++ 80 +++ 109 ++138 + 23 +++ 52 ++++ 81 +++ 110 +++++ 139 + 24 +++++ 53 ++ 82 +++ 111+++ 140 + 25 +++++ 54 +++ 83 ++ 112 ++ 141 + 26 ++++ 55 +++ 84 ++ 113 ++142 ++ 27 ++ 56 +++ 85 ++ 114 ++ 143 + 28 +++++ 57 +++ 86 ++ 115 + 144++ 29 +++++ 58 +++ 87 +++ 116 + 145 ++ 146 +++ 147 + 148 ++ 149 ++ 150+++++ 151 ++++ 152 ++ 153 + 154 ++ 155 +++ 156 +++ 157 ++ 158 + 159 +160 + 161 + 162 ++ 163 + 164 ++ 165 ++++ 166 +++ 167 +++ 168 +++ 169 +++170 +++ 171 +++ 172 +++ 173 +++ 174 +++ 175 +++ 176 +++ 177 +++ 178 +++179 +++ 180 +++ 181 +++ 182 ++ 183 +++ 184 ++ 185 +++ 186 ++ 187 ++ 188+++++ 189 ++++ 190 ++++ 191 ++++ 192 ++++ 193 ++++ 194 +++ 195 +++ 196++++ 197 +++ 198 +++ 199 +++ 200 +++ 201 ++ 202 +++ 203 +++ 204 ++ 205++ 206 ++++ 207 +++ 208 ++++ 209 ++++ 210 +++ 211 +++ 212 +++ 213 ++ 214++ 215 + 216 ++++ 217 +++ 218 ++++ 219 ++++ 220 +++ 221 +++ 222 +++++223 ++++ 224 ++ 225 +++ 226 +++ 227 ++ 228 ++ 229 ++++ 230 ++++ 231 ++232 ++ 233 + 234 + 235 +++++ 236 +++++ 237 +++++ 238 ++++ 239 +++++ 240++++ 241 +++++ 242 +++ 243 ++ 244 +++ 245 +++ 246 ++ 247 ++++ 248 +++249 ++++ 250 +++ 251 ++++ 252 +++ 253 +++++ 254 ++++ 255 +++ 256 +++ 257++ 258 +++ 259 ++ 260 ++ 261 ++ 262 +++ 263 +++ 264 + * in somedeterminations EC₅₀ values were >10 uM ^(#) in some determinations EC₅₀values were <170 pM

NRF2-Keap1 FP Assay

One model for the NRF2-Keap1 interaction is through two binding sites inthe Neh2 domain on NRF2. The two sites are referred to as the DLGbinding motif (latch domain, uM affinity) and the ETGE binding motif(hinge domain, nM affinity). The Keap1 protein consists of an N-terminalregion (NTR), a broad complex, tramtrack, and brick a'brac domain (BTB),an intervening region (IVR), a double glycine repeat domain (DGR orKelch), and a C-terminal region. The DLG and ETGE motifs of NRF2's Neh2domain bind to the Kelch domain of Keap1 at different affinities. In theKeap1 Kelch fluorescence polarization (FP) assay, a TAMRA-labeled 16merpeptide (AFFAQLQLDEETGEFL) containing the ETGE motif of NRF2 and theKelch domain (321-609) of Keap1 is used. The assay determines if acompound interferes with the binding between Keap1 (361-609) and theTAMRA-labeled peptide. Binding of TAMRA-labeled NRF2 peptide to Keap1(321-609) results in a high FP signal. If a compound interferes with thebinding between the peptide and the protein, it will cause the assaysignal to decrease. Thus, assay signal is inversely proportional tobinding inhibition.

FP Assay:

100 nl of 100× compound dose response curves (serial 3-fold dilutions)in DMSO are stamped using an Echo liquid handling system (Labcyte) into384-well low volume black assay plates (Greiner, #784076), with DMSO incolumns 6 and 18. The top concentration of compound is located incolumns 1 and 13. Keap1 (321-609) is diluted to 40 nM (2×) in 1× assaybuffer (50 mM Tris, pH 8.0, 100 mM NaCl, 5 mM MgCl₂, 1 mM DTT, 2 mMCHAPS, and 0.005% BSA) and 5 ul is added using a Multidrop Combi (ThermoElectron Corporation) equipped with a metal tip dispenser to all wellsof the compound plate, except column 18. Column 18 receives only 5 ul ofassay buffer. Immediately, 5 uL of 16 nM (2×) of Tamra labeled peptide(AFFAQLQLDEETGEFL, 21^(st) Century Biochemicals) is added to all wellsof the plate. The plates are spun at 500 rpm for 1 min, incubated for 1hr at room temperature, and read on an Analyst GT (Molecular Devices)equipped with excitation (530/25 nm) and emission (580/10 nm) filtersdesigned for Tamra probes. A 561 nm dichroic mirror is also used in theAnalyst. The final assay concentrations of Keap1 (321-609) and Tamralabelled peptide are 20 nM and 8 nM, respectively. Fluorescencemeasurements, represented as mP, are used in the transformation of thedata. Compound activity is calculated based on percent inhibition,normalized against controls in the assay (Control 1 contains the Tamrapeptide and Keap1 (321-609) together (0% response) and control 2contains the Tamra peptide alone (100% response)). Data analysis ishandled using the software package Abase XE (Surrey, United Kingdom. The% inhibition values are calculated by the equation:

100-(100*((compound response-average control 2)/(average control1-average control2))). For calculation of plC₅₀s,Abase XE uses a fourparameter equation.

All examples described herein possessed activity in the Keap1/NRF2 FPassay.

NRF2-Keap1 TR-FRET Assay

In the NRF2-Keap1 TR-FRET (time-resolved fluorescence resonance energytransfer) assay, full length NRF2 protein and full length Keap1 protein(Keap1 exists a dimer) are used. The assay detects the ability ofcompound to displace the binding of FlagHis-tagged Keap1 withbiotinylated, Avi-tagged NRF2 protein. Biotin-NRF2 binds tostreptavidin-europium (a component of the detection mix) andKeap1-FlagHis is recognized by anti-Flag APC (allophycocyanin) antibody(also a component of the detection mix). If binding occurs between thetwo proteins, there will be an energy transfer from the Eu+3 (donor) at615 nm to the APC (acceptor) at 665 nm. A potential Keap1 inhibitor willcause a reduction in the TR-FRET signal by interfering with the bindingof Keap1 to NRF2.

One hundred nanoliters of 100× compound dose response curves (serial3-fold dilutions) in DMSO are stamped using an Echo liquid handlingsystem (Labcyte) into 384-well, low volume, black assay plates (Greiner,#784076), with DMSO in columns 6 and 18. The top concentration ofcompound is located in columns 1 and 13. All reagents are diluted inassay buffer (50 mM Tris, pH 8.0, 5 mM MgCl2, 100 mM NaCl, 0.005% BSA, 1mM DTT, and 2 mM CHAPS). The BSA, DTT, and CHAPS are added to the assaybuffer on the day of assay. Using a Multidrop Combi (Thermo ElectronCorporation) equipped with a metal tip dispenser, 5 ul of 25 nMKeap1-FlagHis protein is added to all wells of the compound plate, withthe exception of the wells in column 18. Wells in column 18 receive 5 ulof assay buffer instead. Plates are centrifuged at 500 rpm for 1 minute,covered with a plate lid, and incubated at 37° C. for 2.25 hours. Platesare then removed from the incubator and allowed to cool to RT for 15minutes. Five microliters of 50 nM biotin-NRF2 protein is then added toall wells of the plates and the plates are spun at 500 rpm for 1 minute,followed by incubating at 4° C. for 1.25 hours. The plates are thenallowed to warm to RT for 15 minutes, followed by the addition of 10 ulof detection mix (1 nM Streptavidin Eu+W1024 and 5 ug/ml mouseanti-DYKDDDDK IgG conjugated to SureLight APC antibody; both fromColumbia Biosciences) to all wells. Plates are spun at 500 rpm for 1minute, incubated for 1 hour at RT, and read on an Envision plate readerusing a 320 nm excitation filter and 615 nm and 665 nm emission filters.Compound response (% inhibition) and potency (plC50) are calculatedbased on the ratio of the two emissions (665 nm/615 nm) and then thetransformed data is normalized against controls in the assay (control1=1% DMSO in the presence of NRF2 and Keap1 protein and control 2=1%DMSO in the absence of protein). Data analysis is handled using thesoftware package Abase XE (Surrey, United Kingdom). The % inhibitionvalues are calculated from the ratio (transformed) data by the equation:

100−(100*(compound response-average control 2)/(average control1-average control2)).

For calculation of plC50s, Abase XE uses a four parameter equation.

Methods of Use

The compounds of Formula (I) are useful in treating respiratory andnon-respiratory disorders, including COPD, asthma, fibrosis, chronicasthma, acute asthma, lung disease secondary to environmental exposures,acute lung infection, chronic lung infection, al antitrypsin disease,cystic fibrosis, autoimmune diseases, diabetic nephropathy, chronickidney disease, sepsis-induced acute kidney injury, acute kidney injury(AKI), kidney disease or malfunction seen during kidney transplantation,Pulmonary Arterial Hypertension, atherosclerosis, hypertension, heartfailure, acute coronary syndrome, myocardial infarction, myocardialrepair, cardiac remodeling, cardiac arrhythmias, heart failure withpreserved ejection fraction, heart failure with reduced ejectionfraction, diabetic cardiomyopathy, Parkinson's disease (PD), Alzheimer'sdisease (AD), Friedreich's Ataxia (FA), amyotrophic lateral sclerosis(ALS), multiple sclerosis (MS), inflammatory bowel disease, coloncancer, neovascular (dry) AMD and neovascular (wet) AMD, eye injury,Fuchs Endothelial Corneal Dystrophy (FECD), uveitis or otherinflammatory eye conditions, Non-alcoholic Steatohepatitis (NASH),toxin-induced liver disease (e.g., acetaminophen-induced hepaticdisease), viral hepatitis, cirrhosis, psoriasis, dermatitis/topicaleffects of radiation, immunosuppression due to radiation exposure,Preeclampsia, and high altitude sickness, said disorders are treated byadministering to a human in need thereof, a compound of Formula (I).Accordingly, in another aspect the invention is directed to methods oftreating such conditions.

In one embodiment, the compounds of Formula (I) are useful in treatingrespiratory disorders including COPD, asthma, including chronic asthmaand acute asthma.

In one embodiment, the compounds of Formula (I) are useful in treatinghypertension, heart failure, acute coronary syndrome, myocardialinfarction, myocardial repair, cardiac remodeling, cardiac arrhythmias,heart failure with preserved ejection fraction, heart failure withreduced ejection fraction and diabetic cardiomyopathy.

The methods of treatment of the invention comprise administering a safeand effective amount of a compound according to Formula I or apharmaceutically-acceptable salt thereof to a patient in need thereof.

As used herein, “treat” in reference to a condition means: (1) toameliorate or prevent the condition or one or more of the biologicalmanifestations of the condition, (2) to interfere with (a) one or morepoints in the biological cascade that leads to or is responsible for thecondition or (b) one or more of the biological manifestations of thecondition, (3) to alleviate one or more of the symptoms or effectsassociated with the condition, or (4) to slow the progression of thecondition or one or more of the biological manifestations of thecondition.

The skilled artisan will appreciate that “prevention” is not an absoluteterm. In medicine, “prevention” is understood to refer to theprophylactic administration of a drug to substantially diminish thelikelihood or severity of a condition or biological manifestationthereof, or to delay the onset of such condition or biologicalmanifestation thereof.

As used herein, “safe and effective amount” in reference to a compoundof the invention or other pharmaceutically-active agent means an amountof the compound sufficient to treat the patient's condition but lowenough to avoid serious side effects (at a reasonable benefit/riskratio) within the scope of sound medical judgment. A safe and effectiveamount of a compound will vary with the particular compound chosen (e.g.consider the potency, efficacy, and half-life of the compound); theroute of administration chosen; the condition being treated; theseverity of the condition being treated; the age, size, weight, andphysical condition of the patient being treated; the medical history ofthe patient to be treated; the duration of the treatment; the nature ofconcurrent therapy; the desired therapeutic effect; and like factors,but can nevertheless be routinely determined by the skilled artisan.

As used herein, “patient” refers to a human or other animal.

The compounds of the invention may be administered by any suitable routeof administration, including both systemic administration and topicaladministration. Systemic administration includes oral administration,parenteral administration, transdermal administration, rectaladministration, and administration by inhalation. Parenteraladministration refers to routes of administration other than enteral,transdermal, or by inhalation, and is typically by injection orinfusion. Parenteral administration includes intravenous, intramuscular,and subcutaneous injection or infusion. Inhalation refers toadministration into the patient's lungs whether inhaled through themouth or through the nasal passages. Topical administration includesapplication to the skin as well as intraocular, otic, intravaginal, andintranasal administration.

The compounds of the invention may be administered once or according toa dosing regimen wherein a number of doses are administered at varyingintervals of time for a given period of time. For example, doses may beadministered one, two, three, or four times per day. Doses may beadministered until the desired therapeutic effect is achieved orindefinitely to maintain the desired therapeutic effect. Suitable dosingregimens for a compound of the invention depend on the pharmacokineticproperties of that compound, such as absorption, distribution, andhalf-life, which can be determined by the skilled artisan. In addition,suitable dosing regimens, including the duration such regimens areadministered, for a compound of the invention depend on the conditionbeing treated, the severity of the condition being treated, the age andphysical condition of the patient being treated, the medical history ofthe patient to be treated, the nature of concurrent therapy, the desiredtherapeutic effect, and like factors within the knowledge and expertiseof the skilled artisan. It will be further understood by such skilledartisans that suitable dosing regimens may require adjustment given anindividual patient's response to the dosing regimen or over time asindividual patient needs change.

Typical daily dosages may vary depending upon the particular route ofadministration chosen. Typical dosages for oral administration rangefrom 1 mg to 1000 mg per person per day. Preferred dosages are 1-500 mgonce daily, more preferred is 1-100 mg per person per day. IV dosagesrange form 0.1-000 mg/day, preferred is 0.1-500 mg/day, and morepreferred is 0.1-100 mg/day. Inhaled daily dosages range from 10 ug-10mg/day, with preferred 10 ug-2 mg/day, and more preferred 50 ug-500ug/day.

Additionally, the compounds of the invention may be administered asprodrugs. As used herein, a “prodrug” of a compound of the invention isa functional derivative of the compound which, upon administration to apatient, eventually liberates the compound of the invention in vivo.Administration of a compound of the invention as a prodrug may enablethe skilled artisan to do one or more of the following: (a) modify theonset of the compound in vivo; (b) modify the duration of action of thecompound in vivo; (c) modify the transportation or distribution of thecompound in vivo; (d) modify the solubility of the compound in vivo; and(e) overcome a side effect or other difficulty encountered with thecompound. Typical functional derivatives used to prepare prodrugsinclude modifications of the compound that are chemically orenzymatically cleaved in vivo. Such modifications, which include thepreparation of phosphates, amides, ethers, esters, thioesters,carbonates, and carbamates, are well known to those skilled in the art.

Compositions

The compounds of the invention will normally, but not necessarily, beformulated into pharmaceutical compositions prior to administration to apatient. Accordingly, in another aspect the invention is directed topharmaceutical compositions comprising a compound of the invention andone or more pharmaceutically-acceptable excipient.

The pharmaceutical compositions of the invention may be prepared andpackaged in bulk form wherein a safe and effective amount of a compoundof the invention can be extracted and then given to the patient such aswith powders or syrups. Alternatively, the pharmaceutical compositionsof the invention may be prepared and packaged in unit dosage formwherein each physically discrete unit contains a safe and effectiveamount of a compound of the invention. When prepared in unit dosageform, the pharmaceutical compositions of the invention typically containfrom 1 mg to 1000 mg.

The pharmaceutical compositions of the invention typically contain onecompound of the invention. However, in certain embodiments, thepharmaceutical compositions of the invention contain more than onecompound of the invention. For example, in certain embodiments thepharmaceutical compositions of the invention contain two compounds ofthe invention. In addition, the pharmaceutical compositions of theinvention may optionally further comprise one or more additionalpharmaceutically active compounds.

As used herein, “pharmaceutically-acceptable excipient” means apharmaceutically acceptable material, composition or vehicle involved ingiving form or consistency to the pharmaceutical composition. Eachexcipient must be compatible with the other ingredients of thepharmaceutical composition when commingled such that interactions whichwould substantially reduce the efficacy of the compound of the inventionwhen administered to a patient and interactions which would result inpharmaceutical compositions that are not pharmaceutically acceptable areavoided. In addition, each excipient must of course be of sufficientlyhigh purity to render it pharmaceutically-acceptable.

The compound of the invention and the pharmaceutically-acceptableexcipient or excipients will typically be formulated into a dosage formadapted for administration to the patient by the desired route ofadministration. For example, dosage forms include those adapted for (1)oral administration such as tablets, capsules, caplets, pills, troches,powders, syrups, elixers, suspensions, solutions, emulsions, sachets,and cachets; (2) parenteral administration such as sterile solutions,suspensions, and powders for reconstitution; (3) transdermaladministration such as transdermal patches; (4) rectal administrationsuch as suppositories; (5) inhalation such as dry powders, aerosols,suspensions, and solutions; and (6) topical administration such ascreams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically-acceptable excipients will vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically-acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically-acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically-acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically-acceptable excipients may be chosen for their abilityto facilitate the carrying or transporting of the compound or compoundsof the invention once administered to the patient from one organ, orportion of the body, to another organ, or portion of the body. Certainpharmaceutically-acceptable excipients may be chosen for their abilityto enhance patient compliance.

Suitable pharmaceutically-acceptable excipients include the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweeteners, flavoring agents, flavor masking agents, coloring agents,anticaking agents, hemectants, chelating agents, plasticizers, viscosityincreasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically-acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what otheringredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically-acceptable excipients inappropriate amounts for use in the invention. In addition, there are anumber of resources that are available to the skilled artisan whichdescribe pharmaceutically-acceptable excipients and may be useful inselecting suitable pharmaceutically-acceptable excipients. Examplesinclude Reminqton's Pharmaceutical Sciences (Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited), andThe Handbook of Pharmaceutical Excipients (the American PharmaceuticalAssociation and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Reminqton'sPharmaceutical Sciences (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage formsuch as a tablet or capsule comprising a safe and effective amount of acompound of the invention and a diluent or filler. Suitable diluents andfillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch(e.g. corn starch, potato starch, and pre-gelatinized starch), celluloseand its derivatives (e.g. microcrystalline cellulose), calcium sulfate,and dibasic calcium phosphate. The oral solid dosage form may furthercomprise a binder. Suitable binders include starch (e.g. corn starch,potato starch, and pre-gelatinized starch), gelatin, acacia, sodiumalginate, alginic acid, tragacanth, guar gum, povidone, and celluloseand its derivatives (e.g. microcrystalline cellulose). The oral soliddosage form may further comprise a disintegrant. Suitable disintegrantsinclude crospovidone, sodium starch glycolate, croscarmelose, alginicacid, and sodium carboxymethyl cellulose. The oral solid dosage form mayfurther comprise a lubricant. Suitable lubricants include stearic acid,magnesium stearate, calcium stearate, and talc.

In another aspect, the invention is directed to a dosage form adaptedfor administration to a patient parenterally including subcutaneous,intramuscular, intravenous or intradermal. Pharmaceutical formulationsadapted for parenteral administration include aqueous and non-aqueoussterile injection solutions which may contain anti-oxidants, buffers,bacteriostats, and solutes that render the formulation isotonic with theblood of the intended recipient; and aqueous and non-aqueous sterilesuspensions which may include suspending agents and thickening agents.The formulations may be presented in unit-dose or multi-dose containers,for example sealed ampules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injections, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules, and tablets.

In another aspect, the invention is directed to a dosage form adaptedfor administration to a patient by inhalation. For example, the compoundof the invention may be inhaled into the lungs as a dry powder, anaerosol, a suspension, or a solution.

Dry powder compositions for delivery to the lung by inhalation typicallycomprise a compound of the invention as a finely divided powder togetherwith one or more pharmaceutically acceptable excipients as finelydivided powders. Pharmaceutically acceptable excipients particularlysuited for use in dry powders are known to those skilled in the art andinclude lactose, starch, mannitol, and mono-, di-, and polysaccharides.

The dry powder compositions for use in accordance with the presentinvention are administered via inhalation devices. As an example, suchdevices can encompass capsules and cartridges of for example gelatin, orblisters of, for example, laminated aluminum foil. In variousembodiments, each capsule, cartridge or blister may contain doses ofcomposition according to the teachings presented herein. Examples ofinhalation devices can include those intended for unit dose ormulti-dose delivery of composition, including all of the devices setforth herein. As an example, in the case of multi-dose delivery, theformulation can be pre-metered (e.g., as in Diskus®, see GB2242134, U.S.Pat. Nos. 6,032,666, 5,860,419, 5,873,360, 5,590,645, 6,378,519 and6,536,427 or Diskhaler, see GB 2178965, 2129691 and 2169265, U.S. Pat.Nos. 4,778,054, 4,811,731, 5,035,237) or metered in use (e.g. as inTurbuhaler, see EP 69715, or in the devices described in U.S. Pat. No.6,321,747). An example of a unit-dose device is Rotahaler (see GB2064336). In one embodiment, the Diskus® inhalation device comprises anelongate strip formed from a base sheet having a plurality of recessesspaced along its length and a lid sheet peelably sealed thereto todefine a plurality of containers, each container having therein aninhalable formulation containing the compound optionally with otherexcipients and additive taught herein. The peelable seal is anengineered seal, and in one embodiment the engineered seal is a hermeticseal. Preferably, the strip is sufficiently flexible to be wound into aroll. The lid sheet and base sheet will preferably have leading endportions which are not sealed to one another and at least one of theleading end portions is constructed to be attached to a winding means.Also, preferably the engineered seal between the base and lid sheetsextends over their whole width. The lid sheet may preferably be peeledfrom the base sheet in a longitudinal direction from a first end of thebase sheet.

A dry powder composition may also be presented in an inhalation devicewhich permits separate containment of two different components of thecomposition. Thus, for example, these components are administrablesimultaneously but are stored separately, e.g. in separatepharmaceutical compositions, for example as described in WO 03/061743 A1WO 2007/012871 A1 and/or WO2007/068896. In one embodiment an inhalationdevice permitting separate containment of components is an inhalerdevice having two peelable blister strips, each strip containingpre-metered doses in blister pockets arranged along its length, e.g.,multiple containers within each blister strip. Said device has aninternal indexing mechanism which, each time the device is actuated,peels opens a pocket of each strip and positions the blisters so thateach newly exposed dose of each strip is adjacent to the manifold whichcommunicates with the mouthpiece of the device. When the patient inhalesat the mouthpiece, each dose is simultaneously drawn out of itsassociated pocket into the manifold and entrained via the mouthpieceinto the patient's respiratory tract. A further device that permitsseparate containment of different components is DUOHALER™ of Innovata.In addition, various structures of inhalation devices provide for thesequential or separate delivery of the pharmaceutical composition(s)from the device, in addition to simultaneous delivery.

Aerosols may be formed by suspending or dissolving a compound of theinvention in a liquefied propellant. Suitable propellants includehalocarbons, hydrocarbons, and other liquefied gases. Representativepropellants include: trichlorofluoromethane (propellant 11),dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane(propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane(HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12),heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane,perfluoropentane, butane, isobutane, and pentane. Aerosols comprising acompound of the invention will typically be administered to a patientvia a metered dose inhaler (MDI). Such devices are known to thoseskilled in the art.

The aerosol may contain additional pharmaceutically acceptableexcipients typically used with multiple dose inhalers such assurfactants, lubricants, cosolvents and other excipients to improve thephysical stability of the formulation, to improve valve performance, toimprove solubility, or to improve taste.

Suspensions and solutions comprising a compound of the invention mayalso be administered to a patient via a nebulizer. The solvent orsuspension agent utilized for nebulization may be any pharmaceuticallyacceptable liquid such as water, aqueous saline, alcohols or glycols,e.g., ethanol, isopropyl alcohol, glycerol, propylene glycol,polyethylene glycol, etc. or mixtures thereof. Saline solutions utilizesalts which display little or no pharmacological activity afteradministration. Both organic salts, such as alkali metal or ammoniumhalogen salts, e.g., sodium chloride, potassium chloride or organicsalts, such as potassium, sodium and ammonium salts or organic acids,e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc. maybe used for this purpose.

Other pharmaceutically acceptable excipients may be added to thesuspension or solution. The compound of the invention may be stabilizedby the addition of an inorganic acid, e.g., hydrochloric acid, nitricacid, sulfuric acid and/or phosphoric acid; an organic acid, e.g.,ascorbic acid, citric acid, acetic acid, and tartaric acid, etc., acomplexing agent such as EDTA or citric acid and salts thereof; or anantioxidant such as antioxidant such as vitamin E or ascorbic acid.These may be used alone or together to stabilize the compound of theinvention. Preservatives may be added such as benzalkonium chloride orbenzoic acid and salts thereof. Surfactant may be added particularly toimprove the physical stability of suspensions. These include lecithin,disodium dioctylsulphosuccinate, oleic acid and sorbitan esters.

The compounds of Formula (I) and pharmaceutically acceptable saltsthereof may be used in combination with one or more other agents whichmay be useful in the prevention or treatment of allergic disease,inflammatory disease, autoimmune disease, for example; antigenimmunotherapy, anti-histamines, corticosteroids, (eg fluticasonepropionate, fluticasone furoate, beclomethasone dipropionate,budesonide, ciclesonide, mometasone furoate, triamcinolone,flunisolide), NSAIDs, leukotriene modulators (e.g. montelukast,zafirlukast, pranlukast), iNOS inhibitors, tryptase inhibitors, IKK2inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such aselastase inhibitors, integrin antagonists (e.g., beta-2 integrinantagonists), adenosine A2a agonists, mediator release inhibitors suchas sodium chromoglycate, 5-lipoxygenase inhibitors (zyflo), DP1antagonists, DP2 antagonists, PI3K delta inhibitors, ITK inhibitors, LP(lysophosphatidic) inhibitors or FLAP (5-lipoxygenase activatingprotein) inhibitors (e.g. sodium3-(3-(tert-butylthio)-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-((5-methylpyridin-2-yl)methoxy)-1H-indol-2-yl)-2,2-dimethylpropanoate), bronchodilators (e.g.,muscarinic antagonists, beta-2 agonists), methotrexate, and similaragents; monoclonal antibody therapy such as anti-lgE, anti-TNF,anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; cytokinereceptor therapies e.g. etanercept and similar agents; antigennon-specific immunotherapies (e.g. interferon or othercytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4or CXCR2 antagonists, other cytokine/chemokine agonists or antagonists,TLR agonists and similar agents).

The compounds may also be used in combination with agents for aidingtransplantation including Cyclosporines, Tacrolimus, Mycophenolatemofetil, Prednisone, Azathioprine, Sirolimus, Daclizumab, Basiliximab,or OKT3.

They may also be used in combination with agents for Diabetes: metformin(biguanides), meglitinides, sulfonylureas, DPP-4 inhibitors,Thiazolidinediones, Alpha-glucosidase inhibitors, Amylin mimetics,Incretin mimetics, insulin.

The compounds may be used in combination with antihypertensives such asdiuretics, ACE inhibitors, ARBS, calcium channel blockers, and betablockers.

One embodiment of the invention encompasses combinations comprising oneor two other therapeutic agents. It will be clear to a person skilled inthe art that, where appropriate, the other therapeutic ingredient(s) maybe used in the form of salts, for example as alkali metal or amine saltsor as acid addition salts, or prodrugs, or as esters, for example loweralkyl esters, or as solvates, for example hydrates to optimize theactivity and/or stability and/or physical characteristics, such assolubility, of the therapeutic ingredient. It will be clear also that,where appropriate, the therapeutic ingredients may be used in opticallypure form.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable diluent or carrier represent a furtheraspect of the invention.

The individual compounds of such combinations may be administered eithersequentially or simultaneously in separate or combined pharmaceuticalformulations. In one embodiment, the individual compounds will beadministered simultaneously in a combined pharmaceutical formulation.Appropriate doses of known therapeutic agents will readily beappreciated by those skilled in the art.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a compound of the inventiontogether with another therapeutically active agent.

EXAMPLES

The invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention. All temperatures aregiven in degrees Celsius, all solvents are highest available purity andall reactions run under anhydrous conditions in an argon (Ar) ornitrogen (N₂) atmosphere where necessary.

Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layerplates were used for thin layer chromatography. Both flash and gravitychromatography were carried out on silica gel 230-400, 100-200 & 60-120Cilicant Brand. The CombiFlash® system used for purification in thisapplication was purchased from Isco, Inc. CombiFlash® purification wascarried out using prepacked silica gel columns, a detector with UVwavelength at 254 nm and a variety of solvents or solvent combinations.

Preparative HPLC was performed using a Gilson or Waters PreparativeSystem with variable wavelength UV detection or an Agilent Mass DirectedAutoPrep (MDAP) system or Shimadzu PREP LC 20AP with both mass andvariable wavelength UV detection. A variety of reverse phase columns,e.g., Luna C18(2), SunFire C18, XBridge C18, Atlantics T3, Kromasil C18,Xbridge Phenyl-Hexyl columns were used in the purification with thechoice of column support dependent upon the conditions used in thepurification. The compounds are eluted using a gradient of CH₃CN ormethanol and water. Neutral conditions used an CH₃CN and water gradientwith no additional modifier, acidic conditions used an acid modifier,usually 0.1% TFA or 0.1% formic acid and basic conditions used a basicmodifier, usually 0.1% NH₄OH (added to the water) or 10 mM ammoniumbicarbonate (added to the water), or 0.05% NH₄HCO₃ (added to water).

Analytical HPLC was run using an Agilent system or Waters Alliance HPLCwith 2996 PDA detector, Waters Acquity UPLC-MS or Agilent Infinity 1290with PDA or conducted on a Sunfire C18 column, alternative on XSELECTCSH C18 column using reverse phase chromatography with a CH₃CN and watergradient with 0.1% formic acid modifier (added to each solvent) andbasic conditions used a basic modifier, usually 5 mM ammoniumbicarbonate or 10 mM ammonium bicarbonate in water adjusted pH to 10with ammonia solution. The compound was analyzed by LCMS using aShimadzu LC system with UV 214 nm wavelength detection and H₂O— CH₃CNgradient elution (4-95% over 1.9 min.) acidified to 0.02% TFA. Thereversed-phase column was a 2.1×20 mm Thermo Hypersil Gold C₁₈ (1.9 uparticles) at 50° C. The single quadrupole MS detector was either aSciex 150EX or a Waters ZQ operated in positive-ion. Alternatively,LC-MS was determined using either a PE Sciex Single Quadrupole 150EXLC-MS, or Waters ZQ Single Quadrupole, Waters 3100 Single Quadrupole,Agilent 6130 SQD or Agilent 6120 Single Quadrupole LC-MS instruments.The compound is analyzed using a reverse phase column, e.g., ThermoHypersil Gold C18 and/or Luna C18 eluted using a gradient of CH₃CN andwater with a low percentage of an acid modifier such as 0.02% or 0.1%TFA.

Preparative Chiral SFC was performed using a Thar/Waters Preparative SFCSystem with single wavelength UV detection system. A variety of chiralSFC columns, e.g. Chiralpak IA, IC, AY, AD, IF, OJ were used in thepurification. The compounds are eluted using supercritical fluid CO₂ andco-solvents, such as MeOH, EtOH, IPA, and combination of these solventin different ratio based on the compound. Modifiers (0.1% to 0.4% ofTFA, NH₄OH, DEA, TEA) can be used as needed. Normal phase chromatographyis performed using the above mentioned chiral columns & pyridyl amide,ethyl pyridine achiral columns are used for chiral & achiralpurifications respectively. Modifiers (0.1% of TFA, NH₄OH, DEA) would beused as needed. K PREP Lab 100 G-YMC instruments are used in normalphase preparative scale purifications.

Analytical Chiral SFC was run using a Thar/Waters SFC system withvariable wavelength UV detection. A variety of chiral SFC columns, e.g.Chiralpak IA, IB, IC, ID, IF, AY, AD, OD, C2, AS, OJ, CCL4 were used inthe purification. The compounds are eluted using supercritical fluid CO₂and co-solvents, such as MeOH, EtOH, IPA, and combination of thesesolvent in different ratio based on the compound selectivity. Modifiers(0.1% to 0.4% of TFA, NH₄OH, DEA, TEA) would be used as needed.

Celite® is a filter aid composed of acid-washed diatomaceous silica, andis a registered trademark of Manville Corp., Denver, Colo. Isolute® is afunctionalized silica gel based sorbent, and is a registered trademarkof Biotage AB Corp., Sweden.

Nuclear magnetic resonance spectra were recorded at 400 MHz using aBruker AVANCE 400 or Brucker DPX400 spectrometer or Varian MR400spectrometer. CDCl₃ is deuteriochloroform, DMSO-D₆ ishexadeuteriodimethylsulfoxide, and MeOD is tetradeuteriomethanol, CD₂Cl₂is deuteriodichloromethane. Chemical shifts are reported in parts permillion (6) downfield from the internal standard tetramethylsilane (TMS)or calibrated to the residual proton signal in the NMR solvent (e.g.,CHCl₃ in CDCl₃). Abbreviations for NMR data are as follows: s=singlet,d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets,dt=doublet of triplets, app=apparent, br=broad. J indicates the NMRcoupling constant measured in Hertz.

Heating of reaction mixtures with microwave irradiation was carried outon a Biotage Initiator® microwave reactor, typically employing the highabsorbance setting.

Cartridges or columns containing polymer based functional groups (acid,base, metal chelators, etc) can be used as part of compound workup. The“amine” columns or cartridges are used to neutralize or basify acidicreaction mixtures or products. These include NH₂ Aminopropyl SPE-ed SPECartridges available from Applied Separations and diethylamino SPEcartridges available from United Chemical Technologies, Inc.

Table of Abbreviations [Rh(cod)Cl]2 or [RhCl(cod)]2: di-μ- MeCN:acetonitrile chlorido-bis[η2,η2-(cycloocta-1,5- diene)rhodium ® T3P:2,4,6-tripropyl-1,3,5,2,4,6- Mel: methyl iodide trioxatriphosphorinane2,4,6- trioxide ° C.: degree Celsius MeOH: methanol AcOH: acetic acidmg: milligram(s) ADDP: (E)-diazene-1,2- MgCl₂: magnesium chloridediylbis(piperidin-1-ylmethanone) aq = aqueous MgSO₄: magnesium sulfateBINAP: 2,2′- MHz: megahertz bis(diphenylphosphino)-1,1′- binaphthaleneCDl: Carbonyl dimidazole min: minute(s) CH₂Cl₂: dichloromethane mL:milliliter(s) CH₃CN: acetonitrile mmol: millimole(s) CH₃CN: acetonitrileMS: mass spectroscopy CHCl₃: chloroform N₂: nitrogen gas Cs₂CO₃: cesiumcarbonate Na₂CO₃: sodium carbonate DBU: 1,8-diazabicyclo[5.4.0]undec-Na₂SO₄: sodium sulfate 7-ene DCE: dichloroethane NaBH₃CN or NaCNBH3:sodium cyanoborohydride DCM: dichloromethane NaCl: sodium chloride DIPEAor DIEA: diisopropylethyl NaH: sodium hydride amine DME: dimethyl etherNaHCO₃: sodium bicarbonate DMF: N,N-dimethylformamide NaHMDS: sodiumhexamethyldisilazane DMF-DMA or DMF-dimethyl acetal: NaHSO₄: sodiumbisulfate N,N-dimethylformaide-dimethyl acetal DMSO: dimethyl sulfoxideNaOAc: sodium acetate EDC: 1-ethyl-3-(3- NaOH: sodium hydroxidedimethylaminopropyl)carbodiimide Et₂O: diethyl ether NBS:N-Bromosuccinimide Et₃N: triethylamine nBuLi: n-butyl lithium EtOAc:ethyl acetate NH₄Cl: ammonium chloride EtOH: ethanol NMR: nuclearmagnetic resonance g: gram(s) P(tBu)₃: tri-t-butyl phosphine h: hour(s)Pd(PhP₃)4: tetrakistriphenylphosphine palladium HATU:O-(7-azabenzotriazol-1-yl)- Pd/C: pallidium on carbonN,N,N′,N′-tetramethyluronium hexafluorophosphate HBTU:N,N,N′,N′-tetramethyl-O- Pd₂(dba)₃: (1H-benzotriazol-1-yl)uroniumtris(dibenzylideneacetone)- hexafluorophosphate dipalladium(0) HCl:hydrochloric acid PdCl₂(dppf) or Pd(dppf)Cl2: [1,1′-bis(diphenylphosphino)-ferrocene] dichloropalladium(II) HOAt:1-hydroxy-7- Petrol: petroleum ether azabenzotriazole HPLC: highperformance liquid PS-PPh₃: polymer supported chromatographytriphenylphosphine IPA: isopropyl alcohol PtO₂: platinum(IV) oxideK₂CO₃: potassium carbonate RT: room temperature KOAc: Potassium acetateT3P: 2,4,6-tripropyl-1,3,5,2,4,6- trioxatriphosphorinane-2,4,6- trioxidesolution LAH: lithium aluminum hydride TEA: triethylamine LC: liquidchromatography TFA: trifluoroacetic acid LC-MS: liquid chromatography-TFFH: Tetrafluoroformamidinium mass spectroscopy hexafluorophosphateLiBH₄: lithium borohydride THF: tetrahydrofuran LiHMDS: lithium triflicanhydride: hexamethyldisilazane trifluoromethanesulfonic anhydride LiOH:lithium hydroxide TsOH: p-toluenesulfonic acid M: molar wt %: weightpercent

Intermediate 1 Tert-butyl3-((methylsulfonyl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (1.05 g,5.22 mmol) and triethylamine (0.792 g, 7.83 mmol) in dichloromethane(DCM) (30 mL), methanesulfonyl chloride (0.657 g, 5.74 mmol) was added.The reaction mixture was stirred at 0° C. to 25° C. for 3 h after whichit was washed with water (3×50 mL) and HCl (1 M, 30 mL), dried overMgSO₄, filtered and concentrated to give the title compound tert-butyl3-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.0 g, 3.44 mmol, 65.9%yield) as a yellow oil. LC-MS m/z 302 (M+Na)⁺, 1.54 min (ret. time).

Intermediate 2 Tert-butyl 3-(1H-pyrazol-1-yl)piperidine-1-carboxylate

To a solution of 1H-pyrazole (0.487 g, 7.16 mmol) inN,N-dimethylformamide (DMF) (20 mL) was added sodium hydride (0.258 g,10.74 mmol) in small portions at 0° C. The reaction mixture was stirredat 25° C. for 1 h. tert-Butyl3-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.0 g, 3.58 mmol) wasadded, and the mixture was heated at 100° C. for 16 h. The reactionmixture was quenched with saturated NH₄Cl (10 mL), and extracted withEtOAc (3×30 mL). The organic layer was washed with water (2×10 mL),brine (2×10 mL), dried over MgSO₄ and concentrated. The residue waspurified by silica gel chromatography (petroleum ether/ethylacetate=15%) to give the title compound tert-butyl3-(1H-pyrazol-1-yl)piperidine-1-carboxylate (0.5 g, 1.631 mmol, 45.6%yield) as a yellow oil. LCMS m/z 252.2 (M+H)⁺, 1.61 min (ret. time).

Intermediate 3 3-(1H-Pyrazol-1-yl)piperidine

To a solution of tert-butyl 3-(1H-pyrazol-1-yl)piperidine-1-carboxylate(900 mg, 3.58 mmol) in 1,4-dioxane (10 mL) was added hydrogen chloride(292 mg, 8.00 mmol) in 1,4-dioxane (705 mg). The reaction mixture wasstirred at 25° C. for 1 h. The solvent was removed and the residue waspurified by reverse-phase HPLC (MeOH/0.05% NH₃H₂O/H₂O=38%) to give thetitle compound 3-(1H-pyrazol-1-yl)piperidine (190 mg, 1.257 mmol, 35.1%yield) as a yellow solid. LC-MS m/z 152.2 (M+H)⁺, 1.13 min (ret. time)

Intermediate 4 (5-Bromo-2-methylphenyl)methanol

To a solution of 5-bromo-2-methylbenzoic acid (70 g, 326 mmol) intetrahydrofuran (THF) (700 mL) stirred under nitrogen at 0° C. was addeda toluene solution of borane-methyl sulfide complex (244 mL, 488 mmol)drop wise during 15 min. The reaction mixture was stirred for 16 h. Thereaction was cooled to 0° C. and quenched with methanol (500 mL) dropwise. The reaction mixture was stirred at ambient temperature for 3 hand then concentrated. The crude residue was diluted with ethyl acetate(1 L) and washed with 1N HCl (500 mL), brine solution (500 mL) and driedover Na₂SO₄, filtered and concentrated to give the title compound (49 g,244 mmol, 74.9% yield). ¹H NMR (400 MHz, DMSO) δ=7.52 (d, J=2.6 Hz, 1H),7.31 (dd, J=8.0, 2.2 Hz, 1H), 7.12-7.03 (m, 1H), 5.22 (td, J=5.5, 1.8Hz, 1H), 4.48 (dd, J=5.1, 1.8 Hz, 2H), 2.17 (s, 3H).

Intermediate 5 4-Bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene

To a stirred solution of (5-bromo-2-methylphenyl)methanol (100 g, 497mmol) in dry DMF (800 mL) was added NaH (21.88 g, 547 mmol). After thereaction mixture was stirred for 30 minutes,1-(chloromethyl)-4-methoxybenzene (82 g, 522 mmol) was added at 0° C.and the reaction mixture was stirred for another 2 h at ambienttemperature. The reaction was then diluted with Et₂O (200 mL) and water(200 mL). The organic phase was washed with brine (300 mL) and driedwith Na₂SO₄ and concentrated under reduced pressure. The residue waspurified via silica gel column to yield4-bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene (140 g, 436mmol, 88% yield) as a clear oil. ¹H NMR (400 MHz, CHLOROFORM-d) b ppm2.27 (s, 3H) 3.84 (s, 3H) 4.49 (s, 2H), 4.54 (s, 2H), 6.92 (d, J=8.8,2H), 6.94 (d, J=8.4, 1H), 7.31-7.35 (m, 3H), 7.54 (d, J=2, 1H).

Intermediate 6 3-(4-Methoxybenzyl)oxy)methyl)-4-methylbenzaldehyde

To a stirred solution of4-bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene (80 g, 249mmol) in THF (800 mL) at −78° C. under N₂, 2.5 M n-BuLi in hexane (120mL, 299 mmol) was carefully added. The reaction mixture was stirred at−78° C. for 65 min, and then DMF (38.6 mL, 498 mmol) was added. Thereaction mixture was stirred at −78° C. to 25° C. for another 30 min.The mixture was quenched with saturated NH₄Cl (300 mL), and extractedwith EtOAc (2×500 mL). The organic layer was washed with water (300 mL)and brine (2×100 mL), dried (Na₂SO₄) and concentrated. The residue waswashed with petroleum ether:EtOAc=10/1 (2000 mL) to give the titlecompound (50 g, 185 mmol, 74.3% yield) as a solid. LC-MS m/z 288.1(M+H₂O)⁺, 2.04 min (ret. time).

Intermediate 7(4-Fluoro-2-methylphenyl)(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methanol

To a solution of4-bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene (16.04 g, 49.9mmol) in tetrahydrofuran (THF) (200 mL) was added 2.5 M n-BuLi in hexane(23.98 mL, 59.9 mmol) at −78° C. under N₂ atmosphere. The reactionmixture was stirred at −78° C. for 30 min, then4-fluoro-2-methylbenzaldehyde (6.9 g, 49.9 mmol) in 20 mL of THF wasadded. Then the reaction mixture was stirred at −78° C. for 1 h and atambient temperature for 3 h. 100 mL of NH₄Cl (saturated) was added. Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (3×100 mL). The combined organic layer was washed withbrine (50 mL) and dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel chromatography (petroleum ether/ethylacetate=5:1) to give the title compound (4-fluoro-2-methylphenyl)(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methanol (15 g, 39.4mmol, 79%). LC-MS m/z 363.1 (M+H-18)⁺, 2.18 min (ret. time)

Intermediate 8 Methyl3-(4-fluoro-2-methylphenyl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate

To a solution of(4-fluoro-2-methylphenyl)(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methanol(7.8 g, 20.50 mmol) in dichloromethane (DCM) (100 mL) was added((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (7.15 g, 41.0mmol), then boron trifluoride diethyl etherate (10.09 mL, 82 mmol) wasslowly dropped into the reaction at 0° C. under N₂ protection. Thereaction mixture was stirred at 0° C. for 30 min and at ambienttemperature for 4 h. Then the reaction mixture was poured into the 100mL of saturated NaHCO₃ aqueous solution at 0° C. The organic layer wasseparated and the aqueous layer was extracted with DCM (3×100 mL). Thecombined organic layer was washed with brine (100 mL) and dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography (petroleum ether/ethyl acetate=4:1) to give the titlecompound methyl3-(4-fluoro-2-methylphenyl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(7.0 g, 19.91 mmol, 97%). LCMS m/z 327.2 (M+H−18)⁺, 367.2 (M+23)⁺, 2.10min (ret. time)

Intermediate 9 Pent-4-ynal

DMSO (25.3 mL, 357 mmol) was added to a solution of oxalyl chloride(15.61 mL, 178 mmol) in CH₂Cl₂ (900 mL) at −78° C. After it was stirredfor 15 min, pent-4-yn-1-ol (10 g, 119 mmol) in CH₂Cl₂ (100 mL) was addeddropwise and the reaction mixture was stirred for a further 15 min.Triethylamine (74.6 mL, 535 mmol) was added to the reaction mixturewhich was left to stir for an additional 15 min afterwhich it was warmedto 0° C. and quenched with water (100 mL). The aqueous layer wasextracted with DCM (3×150 mL). The combined organic layer was washedwith water (2×300 mL), brine (300 mL) and dried over Na₂SO₄ andconcentrated under reduced pressure to give the title compoundpent-4-ynal (6.7 g, 82 mmol, 68.6% yield). ¹H NMR (400 MHz, CDCl₃)δ=9.81 (s, 1H), 2.72-2.69 (m, 2H), 2.53-2.50 (m, 2H), 2.00-1.99 (m, 1H).

Intermediate 10 (E)-Ethyl hept-2-en-6-ynoate

To ethyl 2-(diethoxyphosphoryl)acetate (24.03 g, 107 mmol) intetrahydrofuran (THF) (150 mL) was added sodium hydride (4.68 g, 117mmol)) in small portions. After 5 min, pent-4-ynal (8.0 g, 97 mmol) wasadded slowly. The reaction mixture was stirred at ambient temperaturefor 30 min. Then saturated NH₄Cl (200 mL) was added and the mixtureextracted with DCM (200 mL×3). The combined organic layer was washedwith brine (200 mL), dried over MgSO₄ and concentrated. The residue waspurified by silica gel chromatography (petroleum ether/ethylacetate=50:1) to give the title compound (E)-ethyl hept-2-en-6-ynoate(12 g, 79 mmol, 81% yield) as an oil. ¹H NMR (400 MHz, CDCl₃) δ=6.96 (m,1H), 5.9 (d, J=15.6 Hz, 1H), 4.22-4.17 (q, J=14, 6.8, 1H), 2.45-2.36 (m,4H), 2.01 (m, 1H), 1.31-1.27 (m, 3H).

Intermediate 11 (E)-Ethyl5-(1-propyl-1H-1,2,3-triazol-4-yl)pent-2-enoate

A mixture of 1-iodopropane (11.17 g, 65.7 mmol), (E)-ethylhept-2-en-6-ynoate (5.0 g, 32.9 mmol), sodium azide (4.27 g, 65.7 mmol)and copper(I) iodide (2.503 g, 13.14 mmol) in water (10 mL) and THF (20mL) was stirred at 70° C. for 8 h. The reaction mixture was concentratedand the residue was extracted with ethyl acetate (3×50 mL). The combinedorganic layer was dried over MgSO₄, concentrated and purified by silicagel chromatography (petroleum ether/ethyl acetate=1:1) to give the titlecompound (E)-ethyl 5-(1-propyl-1H-1,2,3-triazol-4-yl)pent-2-enoate (2.6g, 10.41 mmol, 31.7% yield) as an oil. LCMS m/z 238.1 (M+H)+, 1.50 (ret.time)

Intermediate 12 7-((1H-Imidazol-2-yl)methyl)-7-azabicyclo[2.2.1]heptane

To a solution of 7-azabicyclo[2.2.1]heptane (860 mg, 8.85 mmol) in1,2-dichloroethane (DCE) (10 mL), 1H-imidazole-2-carbaldehyde (851 mg,8.85 mmol) and acetic acid (0.5 mL) were added. After it was stirred for1 h at ambient temperature, sodium triacetoxyhydroborate (3752 mg, 17.70mmol) was added. The reaction mixture was stirred at 25° C. for 2 h. Thesolvent was evaporated and the residue was adjusted to pH 7 with NH₄OHsolution, then extracted with ethyl acetate (2×20 mL). The crude productwas purified by reverse-phase HPLC (A: 10 mmol/L NH₄HCO₃, B: MeOH) togive the title compound7-((1H-imidazol-2-yl)methyl)-7-azabicyclo[2.2.1]heptane (103 mg, 0.552mmol, 6.24% yield), as a yellow solid. LC-MS m/z 178.2 (M+H)+, 1.12 min(ret. time).

Intermediate 13 8-((1H-imidazol-2-yl)methyl)-8-azabicyclo[3.2.1]octane

To a solution of 8-azabicyclo[3.2.1]octane (860 mg, 7.73 mmol) in1,2-dichloroethane (DCE) (10 mL), 1H-imidazole-2-carbaldehyde (743 mg,7.73 mmol) and acetic acid (0.5 mL) was added. After it was stirred for1 h at ambient temperature, sodium triacetoxyhydroborate (3752 mg, 17.70mmol) was added. The reaction mixture was stirred at 25° C. for 2 h. Thesolvent was evaporated and the residue was adjusted to pH 7 with NH₄OHsolution, then extracted with ethyl acetate (20 mL×2). The crude productwas purified by reverse-phase HPLC (A: 10 mmol/L NH₄HCO₃, B: MeOH) togive the title compound the8-((1H-imidazol-2-yl)methyl)-8-azabicyclo[3.2.1]octane (300 mg, 1.490mmol, 19.26% yield) as a yellow solid. LC-MS m/z 192.3 (M+H)+, 1.27 min(ret. time).

Intermediate 14 Ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)pentanoate

To a solution of (E)-ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)pent-2-enoate (10 g, 44.8 mmol) in1,4-dioxane (80 mL) and water (40 mL) was added(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(22.23 g, 90 mmol) and triethylamine (12.49 mL, 90 mmol). The reactionmixture was stirred for 5 min after whichchloro(1,5-cyclooctadiene)rhodium(I) dimer (1.104 g, 2.239 mmol) wasadded under the protection of nitrogen. The reaction mixture was stirredat 90° C. for 16 h. After it was cooled to ambient temperature, thereaction mixture was quenched with water (10 mL) and extracted withEtOAc (3×80 mL). The combined organic layer was washed with water (2×5mL) and brine (2×5 mL), dried over Na₂SO₄ and concentrated. The residuewas purified by silica gel chromatography (petroleum ether/ethylacetate=65:1) to give the title compound ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)pentanoate(5 g, 13.32 mmol, 29.7% yield) as yellow oil. LC-MS m/z 346.2 (M+H)⁺,1.73 min (ret. time).

Intermediate 15 Ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate

To a solution of ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)pentanoate(4.65 g, 13.46 mmol) in dichloromethane (DCM) (60 mL) at 0° C.,imidazole (1.833 g, 26.9 mmol), DMAP (0.082 g, 0.673 mmol) andtert-butylchlorodimethylsilane (3.04 g, 20.19 mmol) were added. Thereaction mixture was stirred at 0° C. to 25° C. for 2 h. The reactionmixture was quenched with water (15 mL) and extracted with DCM (3×40mL). The combined organic layer was washed with water (2×8 mL), brine(2×8 mL), dried over Na₂SO₄ and concentrated. The residue was purifiedwith silica gel chromatography (petroleum ether/ethyl acetate=30%) togive the title compound ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate(4 g, 8.18 mmol, 60.8% yield) as yellow oil. LC/MS m/z 460.3 (M+H)⁺,1.98 min (ret. time).

Intermediate 16 Tert-butyl 4-ethylidenepiperidine-1-carboxylate

Ethyltriphenylphosphonium bromide (27.9 g, 75 mmol) was addedportionwise to the LiHMDS (75 mL, 75 mmol) in THF (60 mL) at 0° C. Afterthe reaction mixture was stirred at 0° C. for 1 h, a solution oftert-butyl 4-oxopiperidine-1-carboxylate (10.0 g, 50.2 mmol) intetrahydrofuran (THF) (60 mL) was added and stirred for a further 2 h atambient temperature. Brine was added to quench the reaction andextracted with ethyl acetate (2×200 mL). The combined organic layer waswashed with brine, dried over MgSO₄ and concentrated. The residue waspurified by silica gel chromatography (petroleum ether/ethylacetate=10/1) to give the title compound tert-butyl4-ethylidenepiperidine-1-carboxylate (6.2 g, 29.3 mmol, 58.5% yield) asan oil. LC-MS m/z 156.2 (M+H-56)⁺, 2.21 min (ret. time).

Intermediate 17 Tert-Butyl-4-ethylpiperidine-1-carboxylate

A mixture of tert-butyl 4-ethylidenepiperidine-1-carboxylate (6200 mg,29.3 mmol) and Pd/C (1561 mg, 14.67 mmol) in methanol (100 mL) washydrogenated with H₂ balloon for 5 h. The mixture was filtered throughcelite and the organic layer was concentrated to give the title compoundtert-butyl 4-ethylpiperidine-1-carboxylate (6200 mg, 29.1 mmol, 99%yield) as oil. LC-MS m/z 158.1 (M+H)⁺, 2.28 min (ret. time).

Intermediate 18 4-Ethylpiperidine

The mixture of tert-butyl 4-ethylpiperidine-1-carboxylate (6200 mg, 29.1mmol), trifluoroacetic acid (2.239 mL, 29.1 mmol) in dichloromethane(DCM) (50 mL) was stirred at ambient temperature for 5 h. The solventwas concentrated to give the title compound 4-ethylpiperidine (2500 mg,22.08 mmol, 76% yield) as an oil which was carried to the next stepwithout further purification. LC-MS m/z 114.2 (M+H)⁺, 1.03 min (ret.time).

Intermediate 19 1-((1H-Imidazol-2-yl)methyl)-4-ethylpiperidine

To a mixture of 4-ethylpiperidine (1200 mg, 10.60 mmol) and1H-imidazole-2-carbaldehyde (1019 mg, 10.60 mmol) was added titanium(IV)isopropoxide (3.73 mL, 12.72 mmol) dropwise. After it was stirred at 25°C. for 2 h, ethanol (120 mL) and NaCNBH₃ (666 mg, 10.60 mmol) were addedand stirred for another 8 h. Water (2 mL) was added to quench thereaction. The solvent was concentrated. The residue was purified byreverse-phase HPLC (MeOH/0.05% NH₃H₂O/H₂O=50%) to give the titlecompound 1-((1H-imidazol-2-yl)methyl)-4-ethylpiperidine (850 mg, 4.18mmol, 39.4% yield) as a solid. LC-MS m/z 194.2 (M+H)⁺, 1.53 min (ret.time)

Intermediate 20 1-((1H-Imidazol-2-yl)methyl)piperidine

To a solution of 1H-imidazole-2-carbaldehyde (2 g, 20.81 mmol) in1,2-dichloroethane (DCE) (100 mL), piperidine (1.772 g, 20.81 mmol) andacetic acid (0.5 mL) were added. After it was stirred at ambienttemperature for 16 h, NaBH(OAc)₃ (8.82 g, 41.6 mmol) was added. Thereaction mixture was stirred at 25° C. for a further 2 h. The solventwas removed and the residue was purified by reverse-phase HPLC (0.05%NH₄HCO₃/H₂O:CH₃CN=5%-95%) to give the title compound1-((1H-imidazol-2-yl)methyl)piperidine (1.6 g, 9.68 mmol, 46.5% yield)as a yellow solid. LC-MS m/z 166.2 (M+H)⁺, 1.27 min (ret. time)

Intermediate 21 Benzyl 4-methylenepiperidine-1-carboxylate

Methyltriphenylphosphonium bromide (18.38 g, 51.4 mmol) was addedportionwise to LiHMDS (51.4 mL, 51.4 mmol) in THF (60 mL) at 0° C. Afterit was stirred for 1 h, a solution of benzyl4-oxopiperidine-1-carboxylate (10.0 g, 42.9 mmol) in tetrahydrofuran(THF) (60 mL) was added and stirred for a further 2 h. Then brine wasadded to quench the reaction followed by extraction with ethyl acetate(2×200 mL). The organic layer was washed with brine, dried andconcentrated. The residue was purified by silica gel chromatography(petroleum ether/ethyl acetate=10/1) to give the title compound benzyl4-methylenepiperidine-1-carboxylate (8.0 g, 34.6 mmol, 81% yield) as anoil. LC-MS m/z 232.2(M+H)⁺, 2.00 min (ret. time)

Intermediate 22 4-Methylpiperidine

A mixture of benzyl 4-methylenepiperidine-1-carboxylate (8000 mg, 34.6mmol) and Pd/C (1840 mg, 17.29 mmol) in methanol (100 mL) washydrogenated at ambient temperature for 5 h. The mixture was filteredthrough celite and the filtrate was concentrated to give the titlecompound 4-methylpiperidine (3000 mg, 30.2 mmol, 87% yield) as oil.LC-MS: m/z 100.2 (M+H)⁺, 0.32 min (ret. time)

Intermediate 23 1-((1H-Imidazol-2-yl)methyl)-4-methylpiperidine

To a mixture of 4-methylpiperidine (2000 mg, 20.17 mmol) and1H-imidazole-2-carbaldehyde (1938 mg, 20.17 mmol) was added titanium(IV)isopropoxide (7.09 mL, 24.20 mmol) dropwise. After it was stirred at 25°C. for 2 h. ethanol (120 mL) and NaCNBH₃ (1267 mg, 20.17 mmol) wereadded and the reaction stirred for another 8 hrs. Water (2 mL) was addedto quench the reaction. The solid was filtered and the solvent wasconcentrated. The residue was purified by reverse-phase HPLC to give thetitle compound 1-((1H-imidazol-2-yl)methyl)-4-methylpiperidine (1500 mg,7.95 mmol, 39.4% yield) as a solid. LC-MS m/z 180.2 (M+H)⁺, 1.39 min(ret. time)

Intermediate 24 4-((1H-Imidazol-2-yl)methyl)-1,4-oxazepane

To a solution of 1,4-oxazepane (900 mg, 8.90 mmol) in 1,2-dichloroethane(DCE) (10 mL), 1H-imidazole-2-carbaldehyde (855 mg, 8.90 mmol) andacetic acid (0.5 mL) were added. After it was stirred for 1 h, sodiumtriacetoxyborohydride (3772 mg, 17.80 mmol) was added. The reactionmixture was stirred at 25° C. for a further 2 h. The solvent was removedand the residue was purified by reverse-phase HPLC (0.05%NH₄HCO₃/H₂O:CH₃CN=5%-95%) to give the title compound4-((1H-imidazol-2-yl)methyl)-1,4-oxazepane (533 mg, 2.88 mmol, 32.4%yield) as a yellow solid. LC-MS m/z 182.1 (M+H)+, 1.19 min (ret. time)

Intermediate 25 2-(Pyrrolidin-1-ylmethyl)-1H-imidazole

To a solution of 1H-imidazole-2-carbaldehyde (2 g, 20.81 mmol) in1,2-dichloroethane (DCE) (100 mL), pyrrolidine (1.480 g, 20.81 mmol) andacetic acid (0.5 mL) were added. After it was stirred for 16 h atambient temperature, NaBH(OAc)₃ (8.82 g, 41.6 mmol) was added. Thereaction mixture was stirred at 25° C. for 2 h. The solvent was removedand the residue was purified by reverse-phase HPLC (0.05%NH₄HCO₃/H₂O:CH₃CN=5%-95%) to give the title compound2-(pyrrolidin-1-ylmethyl)-1H-imidazole (1 g, 6.48 mmol, 31.1% yield) asa yellow solid. LC-MS m/z 152.3 (M+H)⁺, 1.09 min (ret. time).

Intermediate 26 4-((1H-Imidazol-2-yl)methyl)morpholine

To a solution of 1H-imidazole-2-carbaldehyde (2 g, 20.81 mmol) in1,2-dichloroethane (DCE) (100 mL), morpholine (1.813 g, 20.81 mmol) andacetic acid (0.5 mL) were added. After it was stirred for 16 h atambient temperature, NaBH(OAc)₃ (8.82 g, 41.6 mmol) was added. Thereaction mixture was stirred at 25° C. for 2 h. The solvent was removedand the residue was purified by reverse-phase HPLC (0.05%NH₄HCO₃/H₂O:CH₃CN=5%-95%) to give the title compound4-((1H-imidazol-2-yl)methyl)morpholine (1.2 g, 6.46 mmol, 31.0% yield)as a yellow solid. LC-MS m/z 168.1 (M+H)⁺, 1.09 min (ret. time)

Intermediate 27 (R)-4-((1H-Imidazol-2-yl)methyl)-2-methylmorpholine

To a solution of (R)-2-methylmorpholine (860 mg, 8.50 mmol) in1,2-dichloroethane (DCE) (10 mL), 1H-imidazole-2-carbaldehyde (817 mg,8.50 mmol) and acetic acid (0.5 mL) were added. After it was stirred for1 h, sodium triacetoxyborohydride (3604 mg, 17.00 mmol) was added. Thereaction mixture was stirred at 25° C. for 2 h. The solvent was removedand the residue was purified by reverse-phase HPLC (0.05%NH₄HCO₃/H₂O:CH₃CN=5%-95%) to give the title compound(R)-4-((1H-imidazol-2-yl)methyl)-2-methylmorpholine (930 mg, 5.03 mmol,59.1% yield) as a yellow solid. LC-MS m/z 182.2 (M+H)⁺, 1.21 min (ret.time)

Intermediate 28 2-Bromo-N-methoxy-N-methylacetamide

To a stirred solution of N,O-dimethylhydroxylamine hydrochloride (5 g,51.3 mmol) in diethyl ether (65 mL) and water (65 mL) at ambienttemperature was added K₂CO₃ (7.08 g, 51.3 mmol). The reaction mixturewas cooled to 0° C., 2-bromoacetyl bromide (10.35 g, 51.3 mmol) wasadded slowly. It was stirred for 4 h at ambient temperature. It wasextracted with diethyl ether twice. The organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated to give the titlecompound (5 g, 26.0 mmol, 50.8% yield) as liquid. LC-MS m/z 183.8(M+H)⁺, 1.43 min (ret. time)

Intermediate 292-(4,4-Difluoropiperidin-1-yl)-N-methoxy-N-methylacetamide

To a solution of 4,4-difluoropiperidine hydrochloride (6.93 g, 44.0mmol) in tetrahydrofuran (THF) (80 mL) at 0° C. was added TEA (12.25 mL,88 mmol). The reaction mixture was stirred at ambient temperature for 20min, and then 2-bromo-N-methoxy-N-methylacetamide (8 g, 44.0 mmol) intetrahydrofuran (THF) (80 mL) was added at 0° C. The reaction mixturewas stirred at ambient temperature for 48 h. The reaction mixture wasdiluted with water and extracted with EtOAc twice. The combined organiclayer was washed with brine, dried over Na₂SO₄, filtered and thenconcentrated. The crude compound was purified by silica gelchromatography to give the title compound (6 g, 27.0 mmol, 61.4% yield)as liquid. 1H NMR (400 MHz, cdcl3) δ=3.71 (s, 3H), 3.45 (s, 2H), 3.19(s, 3H), 2.79 (br t, J=5.4 Hz, 4H), 2.16-2.02 (m, 4H).

Intermediate 30 2-(4,4-Difluoropiperidin-1-yl)acetaldehyde

To a solution of2-(4,4-difluoropiperidin-1-yl)-N-methoxy-N-methylacetamide (6 g, 27.0mmol) in tetrahydrofuran (THF) (50 mL) at 0° C. was added LAH (1N inTHF) (25 mL, 27.0 mmol). The reaction mixture was stirred at ambienttemperature for 90 min. The reaction mixture was quenched with saturatedNa₂SO₄ solution at 0° C. The reaction mixture was passed through celiteand extracted with EtOAc (2×200 mL) and brine (100 mL), dried overNa₂SO₄, filtered and concentrated to give the title compound (2 g, 12.26mmol, 45.4% yield). ¹H NMR (400 MHz, CDCl₃) δ=9.89-9.59 (m, 1H), 3.24(d, J=1.1 Hz, 2H), 2.73-2.56 (m, 4H), 2.13-1.92 (m, 4H).

Intermediate 31 1-((1H-Imidazol-2-yl)methyl)-4,4-difluoropiperidine

To a solution of 2-(4,4-difluoropiperidin-1-yl)acetaldehyde (2 g, 12.26mmol) in water (50 mL) at ambient temperature was added glyoxal hydrate(0.515 g, 2.452 mmol) and ammonia (0.265 mL, 12.26 mmol). The reactionwas stirred at ambient temperature for 18 h. The reaction mixture wasdiluted with water and extracted twice with DCM. The organic layer wasdried under anhydrous Na₂SO₄, filtered and concentrated to give thecrude product. The crude compound was purified by silica gelchromatography to give the title compound (300 mg, 1.491 mmol, 12.16%yield) as liquid. LC-MS m/z 202.35 (M+H)⁺, 2.40 min (ret. time).

Intermediate 32 3-Methyl-2-nitrobenzamide

To a solution of 3-methyl-2-nitrobenzoic acid (100 g, 552 mmol) inDichloromethane (DCM) (1000 mL), oxalyl chloride (72.5 mL, 828 mmol) wasadded at 25° C. The reaction mixture was stirred at ambient temperaturefor 1 h. The solvent was removed under reduced pressure. The residue wasdissolved in CH₂Cl₂ (100 mL). The solvent was added to ammoniumhydroxide (1000 mL, 7704 mmol) at ambient temperature and was stirredfor 30 minutes. Then the reaction mixture was extracted with ethylacetate (3×500 mL). The combined organic layer was dried over MgSO₄ andconcentrated to give 67 g (60.6%) of the title compound. LC-MS m/z 181.1(M+H)⁺, 1.40 (ret. time).

Intermediate 33 3-Methyl-2-nitroaniline

To a mixture of NaOH (2.220 g, 55.5 mmol) in water (12 mL), Br₂ (0.322mL, 6.26 mmol) was added at 0° C. Then 3-methyl-2-nitrobenzamide (1 g,5.55 mmol) was added in one portion, and the mixture was warmed slowlyin a water bath. The material soon darked in color, and at 50-55° C.(internal temperature) oil droplets began to separate. The temperaturewas raised gradually to 70° and maintained at this point for one hour. Asolution of 0.7 g. of sodium hydroxide in 4 cc. of water was addedslowly and the temperature was increased to 80° C. for an additionalhour. The reaction was cooled to ambient temperature and extracted withethyl acetate (3×50 mL). The combined organic layer was dried andconcentrated to give 0.7 g (90%) of the title compound. LC-MS m/z 153.1(M+H)⁺, 1.65 (ret. time).

Intermediate 34 4-bromo-3-methyl-2-nitroaniline

A mixture of NBS (51.5 g, 289 mmol), 3-methyl-2-nitroaniline (44 g, 289mmol) and acetic acid (450 mL) was stirred at 110° C. for 1 h. Themixture was cooled to ambient temperature and poured into water (100mL). The solid was collected to give 55 g (78%) of the title compound.LC-MS m/z 230.9 (M+H)⁺, 1.78 (ret. time).

Intermediate 35 4-Bromo-N,3-dimethyl-2-nitroaniline

To a solution of 4-bromo-3-methyl-2-nitroaniline (20 g, 87 mmol) inN,N-dimethylformamide (DMF) (200 mL), NaH (3.81 g, 95 mmol) was added at25° C. The reaction mixture was stirred at 25° C. for 30 minutes. Theniodomethane (12.90 g, 91 mmol) was added. The reaction mixture wasstirred for 12 h. The reaction mixture was poured into water and thesolid was collected to give 18 g (59.4%) of the title compound. LC-MSm/z 247.0 (M+H)⁺, 1.90 (ret. time).

Intermediate 36 4-Bromo-N¹,3-dimethylbenzene-1,2-diamine

To a solution of 4-Bromo-N,3-dimethyl-2-nitroaniline (30 g, 122 mmol) inethanol (600 mL), tin(II) chloride (93 g, 490 mmol), was added. Thereaction mixture was stirred at 75° C. for 2 h. Then the solvent wasadjusted to pH=14 by using 40% NaOH. It was extracted with ethyl acetate(3×500 mL). The combined organic layer was dried over MgSO₄ andconcentrated to give 26 g (39.5%) of the title compound.

Intermediate 37 5-bromo-1,4-dimethyl-1H-benzo[d][1,2,3]triazole

To 4-bromo-N¹,3-dimethylbenzene-1,2-diamine (30 g, 139 mmol) in 17 ml of10% H₂SO₄ at 0° C., sodium nitrite (13.47 g, 195 mmol) was added insmall portions over a 20 minute period. After the reaction mixture wasstirred for 30 minutes further, 200 mL of water was added. The resultingprecipitate was collected by filtration, washed with water and dried.The mother liquid was left to stand 16 h and a second batch ofprecipitate formed, which was collected as before. The combined solidswere purified by silica gel chromatography eluting with ethyl acetate togive the title compound 10 g (21.57%). LC-MS m/z 226.0 (M+H)⁺, 1.71(ret. time).

Intermediate 38 (E)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate

To a solution of 5-bromo-1,4-dimethyl-1H-benzo[d][1,2,3]triazole (10 g,44.2 mmol) in N,N-dimethylformamide (DMF) (20 mL), tri-o-tolylphosphine(2.69 g, 8.85 mmol), methyl acrylate (7.62 g, 88 mmol) and DIPEA (23.18mL, 133 mmol) were added. Then Pd(OAc)₂ (0.993 g, 4.42 mmol) was added.The reaction mixture was stirred at 100° C. for 12 h. The mixture waspoured into water and extracted with ethyl acetate (30 mL). The organiclayer was dried and concentrated to get crude product. It was purifiedby silica gel chromatography column (petroleum ether:ethyl acetate=4:1)to give 8.2 g (76%) of the title compound. LC-MS m/z 246.1 (M+H)⁺, 1.68(ret. time).

Intermediate 39 Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

To a solution of (E)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (1 g, 4.08 mmol)in 1,4-dioxane (30 mL) and water (10 ml) were added(3-(hydroxymethyl)-4-methylphenyl)boronic acid (1.015 g, 6.12 mmol),triethylamine (0.852 mL, 6.12 mmol) and [RhCl(cod)]₂ (0.113 g, 0.204mmol). The resulting reaction mixture was stirred at 90° C. for 18.5 h.The reaction mixture was extracted with EtOAc (3×30 mL). The combinedorganic layer was dried over MgSO₄, filtered, concentrated under reducedpressure, purified by silica gel chromatography to afford the desiredproduct ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(1.1954 g, 3.25 mmol, 80% yield). LC-MS m/z 368 (M+H)+, 0.88 (ret.time).

Intermediate 40 2-methoxy-6-nitroaniline

To a solution of 2-amino-3-nitrophenol (2.55 g, 16.55 mmol) inN,N-dimethylformamide (DMF) (35 mL) was added potassium carbonate (2.52g, 18.20 mmol). The mixture was stirred for 5 min before addingiodomethane (1.138 mL, 18.20 mmol). It was stirred at room temperaturefor 2 h. Water (75 mL) was added to quench the reaction and theprecipitates was collected by filtration, washed with water to give 2.26g of 2-methoxy-6-nitroaniline (81%). LC-MS m/z 168.9 (M+H)⁺, 0.74 (ret.time)

Intermediate 41 4-bromo-2-methoxy-6-nitroaniline

To a solution of 2-methoxy-6-nitroaniline (2.26 g, 13.44 mmol) in aceticacid (50 mL) was added sodium acetate (1.654 g, 20.16 mmol) and bromine(0.762 mL, 14.78 mmol). The mixture was stirred at room temperature for30 min. Water was added (75 mL) to quench the reaction and theprecipitate product was collected by filtration, washed with water anddried over vacuum to give 2.78 g of 4-bromo-2-methoxy-6-nitroaniline(84%). LC-MS m/z 246.9/248.9 (M+H)⁺, 0.93 (ret. time).

Intermediate 42 4-bromo-2-methoxy-N-methyl-6-nitroaniline

To a solution of 4-bromo-2-methoxy-6-nitroaniline (2.76 g, 11.17 mmol)dissolved in N,N-dimethylformamide (DMF) (50 mL) was added sodiumhydride (300 mg, 12.50 mmol) slowly at 0° C. and the reaction mixturewas stirred for 30 min. Then methyl iodide (0.768 mL, 12.29 mmol) wasadded. Water was added (60 mL) to quench the reaction and theprecipitate product was collected by filtration, washed with water anddried over vacuum to give 2.82 g of4-bromo-2-methoxy-N-methyl-6-nitroaniline (97%). LC-MS m/z 260.9/263(M+H)⁺, 1.03 (ret. time).

Intermediate 43 5-bromo-7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazole

To a solution of 4-bromo-2-methoxy-N-methyl-6-nitroaniline (2.82 g,10.80 mmol) in glacial acetic acid (100 ml, 1747 mmol) was added zinc(4.94 g, 76 mmol). The reaction mixture was stirred at room temperaturefor 2 h and 30 min. More zinc (150 mg, 2.294 mmol) was added to themixture and the solution was stirred until the orange color disappeared(around 30 min). The mixture was filtered and the solid was washed withethyl acetate. Then the filtrate was concentrated. The crude product wasdissolved in sulfuric acid (10%) (50 mL, 10.80 mmol), sodium nitrite wasadded (0.745 g, 10.80 mmol) in small portions at 0° C. and the mixturewas stirred at 0° C. for 1 h and 45 min. Water (100 mL) was added toquench the reaction and the precipitate product was collected byfiltration, washed with water and dried under vacuum to give 1.28 g of5-bromo-7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazole (49%). LC-MS m/z241.9/243.9 (M+H)⁺, 0.83 (ret. time).

Intermediate 44 (E)-ethyl3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate

To a solution of 5-bromo-7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazole(974 mg, 4.02 mmol) dissolved into DMF (15 mL) were addedN,N-diisopropylethylamine (2.108 mL, 12.07 mmol), ethyl acrylate (4.29mL, 40.2 mmol), diacetoxypalladium (271 mg, 1.207 mmol) andtri-o-tolylphosphine (980 mg, 3.22 mmol). The reaction mixture washeated in microwave at 150° C. for 2 h. Water was added (50 mL) toquench the reaction. Ethyl acetate was added and the layers wereseparated. Aqueous layer was then extracted with ethyl acetate twice.The combined organic layer was dried with MgSO₄, filtered andconcentrated. It was then purified by silica gel chromatography to give820 mg of (E)-ethyl3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (78%).LC-MS m/z 262 (M+H)⁺, 0.90 (ret. time).

Intermediate 45 Ethyl3-(3-(hydroxymethyl)-4-methylphenyl)-3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of (E)-ethyl3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (790 mg,3.02 mmol) in 1,4-dioxane (10 mL) and water (10 mL) was added[RhCl(cod)]₂ (502 mg, 0.907 mmol),(3-(hydroxymethyl)-4-methylphenyl)boronic acid (1506 mg, 9.07 mmol) andEt₃N (0.969 mL, 6.95 mmol). The mixture was heated in microwave at 150°C. for 45 min. Water (25 mL) and ethyl acetate (25 mL) were added andthe layers were separated. The aqueous layer was extracted with ethylacetate twice. The combined organic layer was dried with MgSO₄,filtered, concentrated and purified by silica gel chromatography to give560 mg of ethyl3-(3-(hydroxymethyl)-4-methylphenyl)-3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(48%). LC-MS m/z 384.1 (M+H)⁺, 0.91 (ret. time).

Intermediate 46 2-Chloro-5-fluoro-3-methylpyridine 1-oxide

To 2-chloro-5-fluoro-3-methylpyridine (100 mg, 0.687 mmol) intrifluoroacetic acid (TFA) (10 mL) was added H₂O₂(0.351 mL, 3.43 mmol)slowly under nitrogen at 70° C. The reaction mixture was stirred at 70°C. for 16 h and concentrated. Water (5 mL) and 20 mL of DCM were added.It was adjusted to pH 7 with 28% ammonium hydroxide solution and thenextracted with DCM (3×20 mL). The combined organic layer was dried withMgSO₄, filtered and concentrated to give the title compound2-chloro-5-fluoro-3-methylpyridine 1-oxide (100 mg, 0.532 mmol, 77%yield). LC-MS m/z 162.0 (M+H)⁺, 1.11 min (ret. Time).

Intermediate 47 2-Chloro-3-methyl-5-(methylamino)-4-nitropyridine1-oxide

To a solution of 2-chloro-5-fluoro-3-methylpyridine 1-oxide (100 mg,0.619 mmol) in H₂SO₄ (5 ml, 94 mmol) at ambient temperature undernitrogen was added potassium nitrate (250 mg, 2.476 mmol) slowly. Thereaction mixture was stirred at 110° C. for 16 h after which it waspoured into 50 mL of ice/water. Solid was filtered and dried with highvacuum to give 2-chloro-5-fluoro-3-methyl-4-nitropyridine 1-oxide (100mg, 0.339 mmol, 54.8% yield) as a yellow solid. A mixture of2-chloro-5-fluoro-3-methyl-4-nitropyridine 1-oxide (100 mg, 0.484 mmol)and methanamine (10 mL, 85 mmol) was stirred at 20° C. for 4 h. After itwas concentrated, 10 mL of water was added. Solid was filtered and driedwith high vacuum to give the title compound2-chloro-3-methyl-5-(methylamino)-4-nitropyridine 1-oxide (100 mg, 0.409mmol, 84% yield) as a yellow solid. LC-MS m/z 218.0 (M+H)⁺, 1.36 min(ret. Time)

Intermediate 48 6-Chloro-N3,5-dimethylpyridine-3,4-diamine

To 2-chloro-3-methyl-5-(methylamino)-4-nitropyridine 1-oxide (100 mg,0.460 mmol) in ethanol (10 mL) at 20° C. under nitrogen was added nickel(27.0 mg, 0.460 mmol) slowly. It was hydrogenated at 40 psi in a Parrvessel at ambient temperature for 16 h. The mixture was filtered and thefiltrate was concentrated to give the title compound6-chloro-N3,5-dimethylpyridine-3,4-diamine (80 mg, 0.308 mmol, 66.9%yield) as a dark solid. LC-MS m/z 172.1 (M+H)⁺, 1.01 min (ret. time).

Intermediate 49 6-Chloro-3,7-dimethyl-3H-[1,2,3]triazolo[4,5-c]pyridine

To a solution of 6-chloro-N3,5-dimethylpyridine-3,4-diamine (80 mg,0.466 mmol) in H₂SO₄ (0.5 mL, 9.38 mmol) solution and 5 mL of water wasadded sodium nitrite (260 mg, 3.77 mmol) in water (5 mL) slowly undernitrogen at 0° C. The reaction mixture was stirred at 0° C. for 4 h.Solid was filtered to give the title compound6-Chloro-3,7-dimethyl-3H-[1,2,3]triazolo[4,5-c]pyridine (50 mg, 0.137mmol, 29.4% yield). LC-MS m/z 183.0 (M+H)⁺, 1.45 min (ret. time).

Intermediate 50 (E)-Ethyl3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)acrylate

A mixture of 6-chloro-3,7-dimethyl-3H-[1,2,3]triazolo[4,5-c]pyridine(100 mg, 0.548 mmol), (E)-ethyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (124 mg, 0.548mmol), tetrakis(triphenylphosphine)palladium(0) (31.6 mg, 0.027 mmol),and potassium carbonate (151 mg, 1.095 mmol) in 1,2-dimethoxyethane(DME) (3 mL) and ethanol (0.3 mL) was heated in microwave at 150° C. for2 h (high absorption). Then the reaction mixture was filtered and thefiltrate was purified by reverse-phase HPLC (MeOH/0.05% NH₃H₂O/H₂O=50%)to give the title compound (E)-ethyl3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)acrylate (15 mg,0.059 mmol, 10.59% yield). LCMS m/z 247.1 (M+H)⁺, 1.67 min (ret. time).

Intermediate 51 (R)-Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

To a solution of (E)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (7.5 g, 30.6mmol) in 1,4-dioxane (60 mL) and water (30 mL) was added(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(15.17 g, 61.2 mmol) and TEA (8.52 mL, 61.2 mmol). The reaction mixturewas stirred for 10 min and then chloro(1,5-cyclooctadiene)rhodium(I)dimer (0.754 g, 1.529 mmol) was added under the protection of nitrogenafter which it was stirred at 90° C. for 16 h. The reaction mixture wasextracted with EtOAc (3×100 mL). The combined organic layer was driedover MgSO₄ and concentrated. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=5:4) to give racemiccompound which was separated by chiral SFC chromatography to give thetitle compound (R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(3.2 g, 8.45 mmol, 27.6% yield). LC-MS m/z 368.2 (M+H)⁺, 1.53 min (ret.time).

Intermediate 52 (R)-Ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of (R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(3.2 g, 8.71 mmol) in dichloromethane (DCM) (30 mL) at 0° C. was addedimidazole (1.186 g, 17.42 mmol), DMAP (0.053 g, 0.435 mmol) andtert-butylchlorodimethylsilane (1.969 g, 13.06 mmol). The reactionmixture was stirred at 0° C. to 25° C. for 2 h. The mixture was quenchedwith water (10 mL) and extracted with DCM (3×20 mL). The combinedorganic layer was washed with water (2×8 mL) and brine (2×8 mL), driedover Na₂SO₄, filtered and concentrated. The residue was purified bysilica gel chromatography (petroleum ether/ethyl acetate=5%) to give thetitle compound (R)-ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(3.2 g, 6.44 mmol, 74.0% yield) as yellow oil. LC-MS m/z 482.2 (M+H)⁺,1.98 min (ret. time).

Intermediate 53(R)-3-(3-(((Tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

To a solution of (R)-ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(3.1 g, 6.44 mmol) in tetrahydrofuran (THF) (5.00 mL)/methanol (10 mL)was added LiOH (0.462 g, 19.31 mmol) in water (5.00 mL). The reactionmixture was stirred at 25° C. for 16 h. Solvent was concentrated. Theresidue was adjusted to pH 5 with 3M HCl (3.0 mL) and extracted withethyl acetate (2×100 mL). The organic phase was washed with water (50mL), dried over sodium sulfate, filtered and evaporated in vacuum togive the title compound(R)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (2.9 g, 4.67 mmol, 72.5% yield) as a yellow oil. LC-MS m/z 454.2min (M+H)⁺, 1.84 (ret. time).

Intermediate 54 (R)-Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of(R)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (2.8 g, 6.17 mmol) in acetonitrile (30 mL) were added(bromomethyl)benzene (1.161 g, 6.79 mmol) and K₂CO₃ (1.706 g, 12.34mmol). The reaction mixture was stirred at 25° C. for 16 h. Solvent wasevaporated and the residue was purified by silica gel chromatography(petroleum ether/ethyl acetate=10:1) to give the title compound(R)-benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(2.5 g, 3.68 mmol, 59.6% yield) as a yellow oil. LC-MS m/z 544.3 (M+H)⁺,2.48 min (ret. time).

Intermediate 55 (3R)-Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate

To a solution of (R)-Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(300 mg, 0.552 mmol) in tetrahydrofuran (THF) (10 mL) at −78° C. wasadded solution of 1 M LDA in THF (118 mg, 1.103 mmol). The wine redsolution was stirred at −78° C. for 45 min and then MeI (0.034 mL, 0.552mmol) was added in one portion. Then the red wine color was turned tolight yellow. The reaction mixture was stirred at −78° C. for 45 minafter which it was diluted with EtOAc (75 mL) and water (25 mL). Theaqueous layer was extracted with EtOAc (25 mL). The combined organiclayer was washed with saturated NaCl (25 mL), dried over Na₂SO₄ andconcentrated. This reaction was repeated 4 times (Total 1.5 g startingmaterial). Those five batches are combined and purified by reverse-phaseHPLC (0.05% HN₄HCO₃/H₂O:CH₃CN=5%-95%) to give the title compound(3R)-benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate(250 mg, 0.426 mmol, 15.44% yield) as a yellow oil. LC-MS m/z 558.3(M+H)⁺, 2.50 min (ret. time).

Intermediate 56 (3R)-Benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate

To a solution of (3R)-benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate(240 mg, 0.430 mmol) in tetrahydrofuran (THF) (10 mL) at 0° C. was addedTBAF (124 mg, 0.473 mmol). The reaction mixture was stirred at 0° C. for1 h. The mixture was quenched with saturated NH₄Cl (20 mL) and extractedwith ethyl acetate (3×50 mL). The organic layer was washed with water(30 mL) and brine (30 mL), dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel TLC (petroleum ether/ethylacetate=3:1) to give the title compound (3R)-benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(154 mg, 0.330 mmol, 77% yield) as a white solid. LC-MS m/z 444.2(M+H)⁺, 1.90 min (ret. time).

Intermediate 57(Z)-((1-(Benzyloxy)prop-1-en-1-yl)oxy)(tert-butyl)dimethylsilane

To a solution of diisopropylamine (19.10 mL, 134 mmol) intetrahydrofuran (THF) (200 mL) at 0° C. was added butyllithium (53.6 mL,134 mmol, 2.5M solution in hexanes). The reaction mixture was stirred at0° C. for 30 min. Then it was cooled to −78° C., benzyl propionate (20g, 122 mmol) in THF (10 mL) and chlorotrimethylsilane (15.88 g, 146mmol) were added. The reaction mixture was stirred at −78° C. for 1 h.After the mixture was warmed to ambient temperature, solvent wasremoved. Water (50 mL) was added and the mixutre was extracted withpetroleum ether (2×150 mL), dried over MgSO₄, filtered and concentrated.The residue was purified by distillation (0.5 Hg, 82-90° C.) to give thetitle compound as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ=7.18-7.07 (m,6H), 4.63 (s, 2H), 1.38 (d, J=2.4 Hz, 3H), 0.03 (s, 9H).

Intermediate 58 Benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2-methylpropanoate

To a solution of (Z)-((1-(benzyloxy)prop-1-en-1-yl)oxy)trimethylsilane(6.79 g, 28.7 mmol) in dry acetonitrile (40 mL) was slowly added DBU(0.029 mL, 0.192 mmol) and 2,2,2-trichloroacetonitrile (1.660 g, 11.50mmol) under N₂ protection. After the mixture was stirred at ambienttemperature for 30 min,(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methanol(4 g, 9.58 mmol) and1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (0.135g, 0.479 mmol) was added into the reaction. The reaction mixture wasstirred at ambient temperature for 2 h. Water (20 mL) was added toquench the reaction. The mixture was extracted with ethyl acetate (3×100mL) and the organic layer was washed with brine, dried over MgSO₄,filtered and concentrated to give the title compound benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2-methylpropanoate(1.2 g, 2.086 mmol, 21.78% yield) which was carried to the next stepwithout further purification. LC-MS m/z 563.8 (M+H)⁺, 1.95 min (ret.time).

Intermediate 59 3-(((4-Methoxybenzyl)oxy)methyl)-4-methylbenzaldehyde

To a solution of4-bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene (80 g, 249mmol) in tetrahydrofuran (THF) (800 mL) at −78° C. under nitrogen,butyllithium (120 mL, 299 mmol) was carefully added. The reactionmixture was stirred at −78° C. for 65 min, and then DMF (38.6 mL, 498mmol) was added. The reaction mixture was stirred at −78° C. to 25° C.for another 30 min. It was quenched with sat. NH₄Cl (300 mL), andextracted with ethyl acetate (2×500 mL), the organic layer was washedwith water (300 mL) and brine (2×100 mL), dried over Na₂SO₄, filteredand concentrated. The residue was washed with petroleum ether/ethylacetate=10/1 (2000 mL) to obtain the title compound3-(((4-methoxybenzyl)oxy)methyl)-4-methylbenzaldehyde (50 g, 185 mmol,74.3% yield) as a solid. LC-MS m/z 288.1 (M+H₂O), 2.044 min (ret. time).

Intermediate 60(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methanol

To a solution of 5-bromo-1,4-dimethyl-1H-benzo[d][1,2,3]triazole (36 g,159 mmol) in dry tetrahydrofuran (THF) (500 mL) was addedtert-butyllithium (147 mL, 191 mmol) at −78° C. under the protection ofnitrogen. It was stirred at −78° C. for 0.5 h. Then a solution of3-(((4-methoxybenzyl)oxy)methyl)-4-methylbenzaldehyde (43.0 g, 159 mmol)in dry tetrahydrofuran (THF) (500 mL) was added into the reactionmixture. After it was stirred at −78° C. for 1.5 hr, the reactionmixture was warmed to 25° C. and continuously stirred for an additional1 h. Saturated NH₄Cl aqueous solution (100 mL) was added to quench thereaction. Then the reaction mixture was extracted with EtOAc (2×300 mL).The combined the organic layer was washed with brine (2×200 mL), driedwith MgSO₄ and concentrated. The residue was purified by silica gelchromatography (EtOAc:PE=1:5) to obtain the title compound(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methanol(24 g, 57.5 mmol, 36.1% yield) as a clear oil. LCMS m/z 418.2 (M+H)⁺,2.05 min (ret. time).

Intermediate 61 Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate

To a solution of(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methanol(15.0 g, 35.9 mmol) in dichloromethane (DCM) (250.0 mL) was added((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (12.53 g, 71.9mmol), then titanium tetrachloride (3.96 mL, 35.9 mmol) in DCM (20 ml)was slowly dropped into the reaction at 0° C. under N₂ protection. Thereaction mixture was stirred at 0° C. for 30 min under N₂ protection,then was warmed to ambient temperature and continuously stirred for anadditional 4 h. Then the reaction mixture was poured into saturatedNaHCO₃ aqueous solution (100 mL) at 0° C. The organic layer wasseparated and the aqueous layer was extracted with DCM (3×50 mL). Thecombined organic layer was washed with brine (100 mL) and dried overanhydrous Na₂SO₄ and concentrated. The residue was purified with asilica gel chromatography (petroleum ether/ethyl acetate=1:1) to obtainthe title compound methyl 3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (3.0 g, 7.63 mmol, 21.23% yield) as a solid. LCMSm/z 382.2 (M+H)+, 1.82 min (ret. time).

Intermediate 62 (S)-Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoateand (R)-methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate

Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(4.5 g, 11.80 mmol) was separated by chiral SFC chromatography to obtainisomer 1-(S)-methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(1.4 g, 3.49 mmol, 29.6%) and isomer 2-(R)-methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(1.1 g, 2.74 mmol, 23.22%).

Intermediate 63 1-((2,3-Difluorobenzyl)amino)-2-methylpropan-2-ol

To a solution of 2,3-difluorobenzaldehyde (10 g, 70.4 mmol) in methanol(100 mL) was added 1-amino-2-methylpropan-2-ol (6.27 g, 70.4 mmol) andNaOH (7.04 mL, 7.04 mmol). It was stirred under nitrogen atmosphere for1 h, and then NaBH₄ (1.065 g, 28.1 mmol) was added portion wise over 10min. The reaction was stirred at ambient temperature for 24 h. The crudeproduct was purified by silica gel chromatography. The fractions wereconcentrated to give the title compound (10 g, 44.0 mmol, 62.5% yield)as an off-white solid. LC-MS: m/z: 216.13(M+H)⁺, 1.915 min (ret. time).

Intermediate 649-Fluoro-2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of 1-((2,3-difluorobenzyl)amino)-2-methylpropan-2-ol (2 g,9.29 mmol) in dimethyl sulfoxide (DMSO) (20 mL) was added potassiumtert-butoxide (2.085 g, 18.58 mmol) and the reaction mixture was stirredat 80° C. for 2 h. The reaction mixture was poured in ice water (100 mL)and extracted with ethyl acetate (2×100 mL). The combined organic layerwas washed with water (2×100 mL), brine (100 mL) and then dried overNa₂SO₄. It was filtered and concentrated. The crude residue was purifiedwith silica gel chromatography to give the title compound (2 g, 5.77mmol, 62.1% yield) as gummy liquid. LC-MS: m/z:196.09 (M+H)⁺, 1.875 min(ret. time).

Intermediate 65 Tert-Butyl9-fluoro-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

To a solution of9-fluoro-2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (5 g,25.6 mmol) in dichloromethane (DCM) (50 mL) at 0° C. was added TEA (7.14mL, 51.2 mmol) and Boc-anhydride (7.73 mL, 33.3 mmol). The reaction wasstirred at ambient temperature for 3 h, diluted with water (100 mL) andextracted with ethyl acetate (2×100 mL), washed with brine solution (100mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The cruderesidue was purified with silica gel chromatography to give the titlecompound (6.5 g, 21.47 mmol, 84% yield) as an off-white solid. LC-MS:m/z: 239.94(M-56)⁺, 6.256 min (ret. time).

Intermediate 669-Fluoro-2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepinehydrochloride

To a solution of tert-butyl9-fluoro-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(6.5 g, 22.01 mmol) in dichloromethane (DCM) (20 mL) at 10° C. was added4 M HCl in 1,4-dioxane (16.51 mL, 66.0 mmol). It was stirred for 1 h.The obtained precipitate was filtered and triturated with hexane, driedwell to give the title compound (4.47 g, 18.99 mmol, 86% yield) as anoff-white solid. LC-MS m/z: 196.0 (M−HCl)⁺, 3.335 min (ret. time).

Intermediate 67 (R)-1-((2-Bromo-3-fluorobenzyl)amino)butan-2-ol

To a solution of 2-bromo-3-fluorobenzaldehyde (600 mg, 2.96 mmol) inmethanol (8 mL) was added (R)-1-aminobutan-2-ol (263 mg, 2.96 mmol) and1 N NaOH (0.5 mL, 0.500 mmol) under nitrogen atmosphere. NaBH₄ (224 mg,5.91 mmol) was added at 0° C. portionwise over 10 min. The reaction wasstirred at ambient temperature for 72 h. The resulting mixture wasconcentrated and the crude residue was purified with silica gelchromatography to give the title compound (600 mg, 2.173 mmol, 73.5%yield) as colorless liquid. LC-MS: m/z 278.17 (M+H)⁺, 1.307 min (ret.time).

Intermediate 68(R)-2-Ethyl-9-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of (R)-1-((2-bromo-3-fluorobenzyl)amino)butan-2-ol (600mg, 2.173 mmol) in isopropanol (15 mL) was added Cs₂CO₃ (601 mg, 4.35mmol) and copper(I) iodide (41.4 mg, 0.217 mmol) and the reactionmixture was stirred at 90° C. in microwave reactor for 48 h. Thereaction mixture was quenched with cold water, extracted twice withEtOAC followed by brine solution. The organic layer was dried overanhydrous Na₂SO₄ and filtered and concentrated. The crude compound waspurified with silica gel chromatography to afford the title compound(300 mg, 1.430 mmol, 65.8% yield) as liquid. LC-MS: m/z 196.21 (M+H)⁺,1.26 min (ret. time).

Intermediate 69(R)-2-Ethyl-9-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepinehydrochloride

To a solution of(R)-2-ethyl-9-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (250 mg,1.281 mmol) in 1,4-dioxane (10 mL) at 0° C. was added 4 M HCl in dioxane(2 mL, 8.00 mmol). The reaction mixture was stirred at ambienttemperature for 3 h. The reaction mixture was concentrated andtriturated with hexane, diethyl ether to give the title compound (280mg, 1.139 mmol, 89% yield) as yellow solid. LC-MS: m/z 196.1 (M+H)⁺, 3.3min (ret. time).

The compounds in Table 1 were prepared by a method similar to the onedescribed for the preparation of(R)-2-Ethyl-9-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepinehydrochloride using potassium tert-butoxide for cyclization. As isappreciated by those skilled in the art, these analogous examples mayinvolve variations in general reaction conditions.

TABLE 1 Ret. Time Reagent Product Name Product Structure (M + H)⁺ (min)

(R)-2-Ethyl-6-fluoro- 2,3,4,5- tetrahydrobenzo[f][1,4] oxazepinehydrochloride

196.1 3.38

(R)-2-Ethyl-8-fluoro- 2,3,4,5- tetrahydrobenzo[f][1,4] oxazepinehydrochloride

196.0 3.38

(R)-2-Ethyl-7-fluoro- 2,3,4,5- tetrahydrobenzo[f][1,4] oxazepinehydrochloride

196.15 1.20

(R)-2-Ethyl-7-methyl- 2,3,4,5- tetrahydrobenzo[f][1,4] oxazepine

192.35 3.02

(R)-7-Chloro-2-ethyl- 2,3,4,5- tetrahydrobenzo[f][1,4] oxazepine

212.17 3.41

(R)-2-Ethyl-9-methyl- 2,3,4,5- tetrahydrobenzo[f][1,4] oxazepine

192.0 3.47

2-Ethyl-8-methoxy- 2,3,4,5- tetrahydrobenzo [f][1,4]oxazepine

1H NMR (400 MHz, D6-DMSO) δ = 7.03 (d, J = 7.9 Hz, 1H), 6.57-6.45 (m,2H), 3.77-3.69 (m, 5H), 3.79-3.61 (m, 1H), 3.55-3.44 (m, 1H), 3.05 (brd, J = 13.4 Hz, 1H), 2.76- 2.66 (m, 1H), 1.60- 1.41 (m, 2H), 1.01 (t, J= 7.3 Hz, 3H).

(R)-2-Ethyl-8-methyl- 2,3,4,5- tetrahydrobenzo[f][1,4] oxazepine

192.35 3.00

2,2-Dimethyl-2,3,4,5- tetrahydrobenzo[f][1,4] oxazepine

178.19 2.72

(R)-2-Ethyl-2,3,4,5- tetrahydropyrido[4,3- f][1,4]oxazepine

179.26 2.37

(R)-2-Ethyl-2,3,4,5- tetrahydrobenzo[f][1,4] oxazepine hydrochloride

178.1 1.563

7-Methoxy-2,2-dimethyl- 2,3,4,5-tetrahydrobenzo [f][1,4] oxazepine

208.1 3.17

7-chloro-2,2-dimethyl- 2,3,4,5-tetrahydrobenzo [f][1,4]oxazepine

212.0 3.49

2,2,8-Trimethyl-2,3,4,5- tetrahydrobenzo[f][1,4] oxazepine

192.20 1.36

7-Fluoro-2,2-dimethyl- 2,3,4,5-tetrahydrobenzo [f][1,4]oxazepine

196.11 1.22

7-Bromo-2,2-dimethyl- 2,3,4,5-tetrahydrobenzo [f][1,4]oxazepine

256.07 1.45

8-Bromo-2,2-dimethyl- 2,3,4,5-tetrahydrobenzo [f][1,4]oxazepine

256.15 1.52

2,2-Dimethyl-2,3,4,5- tetrahydropyrido[3,4- f][1,4]oxazepinehydrochloride

179.0 2.7

(R)-2-Methyl-2,3,4,5- tetrahydrobenzo[f][1, 4]oxazepine hydrochloride

164.23 2.36

(R)-2-Ethyl-6-fluoro- 2,3,4,5-tetrahydropyrido [3,4-f][1,4]oxazepine

197.0 4.3

(R)-6-Bromo-2-ethyl- 2,3,4,5-tetrahydropyrido [3,2-f][1,4]oxazepine

256.9, 258.9 4.23

2,2-dimethyl-2,3,4,5- tetrahydropyrido[4,3- f][1,4]oxazepine

179.0 (M- HCI)⁺ 3.33

Intermediate 70 Tert-Butyl7-bromo-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

To a solution of7-bromo-2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (700 mg,2.73 mmol) in dichloromethane (DCM) (5 mL) at ambient temperature wasadded TEA (0.381 mL, 2.73 mmol). Tert-butyl dicarbonate (596 mg, 2.73mmol) was added at 0° C. The reaction mixture was stirred at ambienttemperature for 1 h. It was diluted with water and extracted with ethylacetate, dried over Na₂SO₄, filtered and concentrated. The crude residuewas purified with silica gel chromatography to give the title compound(900 mg, 2.444 mmol, 89% yield) as liquid. LC-MS m/z 300.13 (M+H)⁺, 4.23min (ret. time).

Intermediate 712,2-Dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carbonitrile

To a solution of tert-butyl7-bromo-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(300 mg, 0.842 mmol) in N,N-dimethylformamide (DMF) (5 mL) at ambienttemperature was added Zn(CN)₂ (99 mg, 0.842 mmol). The reaction mixturewas degassed for 20 min, followed by the addition oftetrakis(triphenylphosphine)palladium(0) (97 mg, 0.084 mmol). Thereaction mixture was heated in microwave reactor for 1 h at 95° C. Thereaction mixture was concentrated and purified with silica gelchromatography to give the title compound (90 mg, 0.101 mmol, 12.02%yield) as liquid. LC-MS m/z 203.21 (M+H)⁺, 1.22 min (ret. time).

Intermediate 72 tert-Butyl7-cyano-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

To a solution of2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carbonitrile(270 mg, 1.335 mmol) and TEA (0.186 mL, 1.335 mmol) in dichloromethane(DCM) (5 mL) at 0° C. was added tert-butyl dicarbonate (291 mg, 1.335mmol). The reaction mixture was stirred at ambient temperature for 1 h.The reaction mixture was diluted with water and extracted with ethylacetate, dried over Na₂SO₄, filtered and concentrated. The crude residuewas purified with silica gel chromatography to give the title compound(300 mg, 0.930 mmol, 69.7% yield) as liquid. LC-MS m/z 247.15 (M+H)⁺,2.63 min (ret. time).

Intermediate 732,2-Dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carbonitrilehydrochloride

To a solution of tert-butyl7-cyano-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(300 mg, 0.992 mmol) in 1,4-dioxane (5 mL) at 0° C. was added 4M HCl indioxane (1 mL, 4.00 mmol). The reaction mixture was stirred at ambienttemperature for 2 h. The reaction mixture was concentrated andtriturated with 1:4 diethyl ether:hexane. It was dried to give the titlecompound (190 mg, 0.776 mmol, 78% yield) as solid. LC-MS m/z 203.24(M+H)⁺, 1.17 min (ret. time).

Intermediate 74 Tert-Butyl8-bromo-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

To a solution of8-bromo-2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (800 mg,3.12 mmol) in dichloromethane (DCM) (15 mL) at 0° C. was added TEA(0.871 mL, 6.25 mmol) and boc-anhydride (0.870 mL, 3.75 mmol). Thereaction was stirred at ambient temperature for 2 h. The reactionmixture was concentrated, and then quenched with ice water and extractedwith DCM twice. The organic layer was dried with Na₂SO₄, filtered, andconcentrated. The crude residue was purified with silica gelchromatography to give the title compound (900 mg, 2.429 mmol, 78%yield) as color less liquid. LC-MS m/z 255.9 (M-Boc)⁺, 4.33 min (ret.time).

Intermediate 752,2-Dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carbonitrile

To a solution of tert-butyl8-bromo-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(450 mg, 1.263 mmol) in N,N-dimethylformamide (DMF) (5 mL) was addedZn(CN)₂ (178 mg, 1.516 mmol). The reaction mixture was degassed for 10min followed by addition of tetrakis(triphenylphosphine)palladium(0)(146 mg, 0.126 mmol). The reaction mixture was heated in microwavereactor for 1 h at 90° C. The reaction mixture was quenched with icewater, extracted twice with EtOAc, washed with water and brine solution.The organic layer was dried over anhydrous Na₂SO₄ and filtered andconcentrated. The crude residue was purified with silica gelchromatography to give the title compound (200 mg, 0.989 mmol, 78%yield). LC-MS m/z 203.16 (M+H)⁺, 1.30 min (ret. time).

Intermediate 76 tert-Butyl8-cyano-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

To a solution of2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carbonitrile(400 mg, 1.978 mmol) in dichloromethane (DCM) (15 mL) at 0° C. was addedTEA (0.551 mL, 3.96 mmol) and BOC-anhydride (0.551 mL, 2.373 mmol). Thereaction was stirred at ambient temperature for 2 h. The reactionmixture was concentrated and quenched with ice water and extracted withtwice DCM. The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated. The crude residue was purified with silica gelchromatography to give the title compound (210 mg, 0.690 mmol, 34.9%yield) as color less liquid. LC-MS m/z 203.0 (M-BOC)⁺, 3.94 min (ret.time).

Intermediate 772,2-Dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carbonitrilehydrochloride

To a solution of tert-butyl8-cyano-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(200 mg, 0.661 mmol) in 1,4-dioxane (5 mL) at 0° C. was added 4M HCl indioxane (1 mL, 4.00 mmol). The reaction was stirred at ambienttemperature for 2 h. The reaction mixture was concentrated andtriturated with diethyl ether to give the title compound (130 mg, 0.537mmol, 81% yield) as yellow solid. LCMS: 203.24 m/z: M+H)⁺, 1.17 min(ret.time)

Intermediate 78 (S)-2-(((2-Hydroxybutyl)amino)methyl)pyridin-3-ol

To a solution of (S)-1-aminobutan-2-ol (0.724 g, 8.12 mmol) in methanol(10 mL) was added NaOH (0.812 mL, 0.812 mmol). After 30 min, NaBH₄(0.246 g, 6.50 mmol) was added at 0° C. The reaction was stirred atambient temperature for 16 h and then concentrated. The crude residuewas dissolved in water (5 mL), extracted with 10% MeOH in DCM. Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated to give the title compound (800 mg, 3.61 mmol, 44.5%yield). LC-MS: m/z 197.0 (M+H)⁺, 2.31 min (ret. time).

Intermediate 79(R)-2-Ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine

To a solution of (S)-2-(((2-hydroxybutyl)amino)methyl)pyridin-3-ol (800mg, 4.08 mmol) in tetrahydrofuran (THF) (15 mL) at 0° C. was addedtriphenylphosphine (1604 mg, 6.11 mmol) and DEAD (0.968 mL, 6.11 mmol).The reaction was stirred at 25° C. for 2 h. The crude residue wasconcentrated and purified with silica gel chromatography to give thetitle compound (250 mg, 0.711 mmol, 17.44% yield). LCMS: m/z-179.0(M+H)⁺, 2.86 min (ret.time)

Intermediate 80 (R)-tert-Butyl2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-carboxylate

To a solution of(R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine (250 mg, 1.403mmol) in dichloromethane (DCM) (5 mL) was added TEA (0.293 mL, 2.104mmol) and BOC-anhydride (0.326 mL, 1.403 mmol). The reaction was stirredat 25° C. for 1 h. It was diluted with water and extracted with DCM(3×10 mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated to give the title compound (200 mg, 0.533mmol, 38.0% yield). LCMS: m/z-279.29 (M+H)⁺, 2.07 min (ret.time)

Intermediate 81(R)-2-Ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine

To a solution of (R)-tert-butyl2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-carboxylate (200mg, 0.719 mmol) in 1,4-dioxane (2 mL) at 0° C. was added 4 M HCl in1,4-dioxane (0.359 mL, 0.719 mmol). The reaction was stirred at ambienttemperature for 1 h. The reaction mixture was concentrated and thendissolved in DCM (20 mL), and washed with saturated NaHCO₃ solution(2×15 mL). The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated to give the title compound (80 mg, 0.282 mmol, 39.3%yield). LCMS: m/z=179.23 (M+H)⁺, 2.66 min (ret.time)

Intermediate 82 1-((2,4-Dibromobenzyl)amino)butan-2-ol

To a solution of 2,4-dibromo-1-(bromomethyl)benzene (700 mg, 2.129 mmol)and 1-aminobutan-2-ol (190 mg, 2.129 mmol) in tetrahydrofuran (THF) (20mL) and water (4.00 mL) at ambient temperature was added K₂CO₃ (441 mg,3.19 mmol). The reaction was stirred for 15 h, diluted with water (20mL) and extracted with EtOAc (2×20 mL). The combined organic layer waswashed with brine solution (20 mL) and dried over anhydrous Na₂SO₄,filtered and concentrated. The crude residue was concentrated andpurified with silica gel chromatography to give the title compound (400mg, 0.900 mmol, 42.3% yield) as a white solid. LCMS: m/z=337.9 (M+H)⁺,3.699 min (ret.time)

Intermediate 83 8-Bromo-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of 1-((2,4-dibromobenzyl)amino)butan-2-ol (400 mg, 1.187mmol) in N,N-dimethylformamide (DMF) (5 mL) in a sealed tube at ambienttemperature were added Cs₂CO₃ (773 mg, 2.374 mmol) and copper(I) iodide(45.2 mg, 0.237 mmol). It was heated at 100° C. for 30 h. The reactionmixture was cooled and diluted with ice water (30 mL). It was extractedwith EtOAc (2×30 mL). The combined organic layer was washed with brinesolution (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude residue was concentrated and purified withsilica gel chromatography to give the title compound (150 mg, 0.471mmol, 39.7% yield). LC-MS: m/z 255.9 (M+H)⁺, 3.585 min (ret. time).

The compounds in Table 2 were prepared by a method similar to the onedescribed for the preparation of8-bromo-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine. As isappreciated by those skilled in the art, these analogous examples mayinvolve variations in general reaction conditions.

TABLE 2 Ret. Time Reagent Product Name Product Structure (M + H)⁺ (min)

2-Ethyl-7-fluoro-2,3,4,5- tetrahydrobenzo[f][1,4] oxazepine

196.01 3.37

6-Chloro-2-ethyl-2,3,4,5- tetrahydrobenzo[f][1,4] oxazepine

212.0 1.57

Intermediate 84 Methyl 2-(2-carbamoylphenoxy)pentanoate

To 2-hydroxybenzamide (500 mg, 3.65 mmol) in tetrahydrofuran (THF) wasadded methyl 2-bromopentanoate (1067 mg, 5.47 mmol) and potassiumcarbonate (504 mg, 3.65 mmol). The resulting reaction mixture was heatedin a Biotage microwave at high absorption for 1.5 h at 120° C. Thereaction was stirred at ambient temperature for 2 days and thenfiltered. It was washed with ethyl acetate. The filtrate wasconcentrated. The crude product was purified by silica gelchromatography. The desired fractions were concentrated to give thetitle compound (750 mg, 2.98 mmol, 82% yield) as white solid. LC-MS m/z251.9 (M+H)⁺, 0.78 min (ret. time).

Intermediate 85 2-Propylbenzo[f][1,4]oxazepine-3,5(2H,4H)-dione

To methyl 2-(2-carbamoylphenoxy)pentanoate (300 mg, 1.194 mmol) inN,N-dimethylformamide (DMF) (3 mL) was added sodium methoxide (2.388 mL,1.194 mmol) slowly. The resulting reaction mixture was stirred atambient temperature for 23 h. The solvent was removed under reducedpressure and the residue was purified by silica gel chromatography togive the title compound (116 mg, 0.529 mmol, 44.3% yield) as whitesolid. LC-MS m/z 220.0 (M+H)⁺, 0.87 min (ret. time).

Intermediate 86 2-Propyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a suspension of LAH (60.2 mg, 1.587 mmol) in tetrahydrofuran (THF) (2mL) was added a solution of2-propylbenzo[f][1,4]oxazepine-3,5(2H,4H)-dione (116 mg, 0.529 mmol) intetrahydrofuran (THF) (2 mL). The mixture was heated in a Biotagemicrowave at high absorption for 1.5 h at 100° C. Saturated Na₂SO₄ (0.26mL) was added dropwise. The mixture was stirred for 30 min. The reactionmixture turned from grey to white solution. The solid was filtered andwashed with ethyl acetate. The filtrate was concentrated to give thetitle compound (100 mg, 0.523 mmol, 99% yield). LC-MS m/z 192.0 (M+H)⁺,0.54 min (ret. time).

The compounds in Table 3 were prepared by a method similar to the onedescribed for the preparation of2-propyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine. As is appreciated bythose skilled in the art, these analogous examples may involvevariations in general reaction conditions.

TABLE 3 LCMS Retention [M + Time Structure Name H]⁺ (min)

2-Isopropyl-2,3, 4,5- tetrahydrobenzo [f][1,4]oxazepine 192.1 0.61

2- (Methoxymethyl)- 2,3,4,5- tetrahydrobenzo [f][1,4]oxazepine 194.00.43

2-Methyl-2,3,4,5- tetrahydrobenzo [f][1,4]oxazepine 163.9 0.42

Intermediate 87 Bromo-2-(chloromethyl)-1-methylbenzene

To a solution of (5-bromo-2-methylphenyl)methanol (5 g, 24.87 mmol) indichloromethane (DCM) (50 mL) at 10° C. was added SOCl₂ (2.72 mL, 37.3mmol). The reaction was stirred for 3 h. It was concentrated and thendiluted with NaHCO₃ solution and extracted with EtOAc (2×20 mL). Thecombined organic layer was washed with brine solution (20 mL), driedover anhydrous Na₂SO₄, filtered and concentrated to give the titlecompound (5 g, 22.78 mmol, 92% yield) as color less liquid. 1H NMR (400MHz, dmso) δ=7.62 (d, J=2.0 Hz, 1H), 7.44 (dd, J=2.2, 8.1 Hz, 1H), 7.20(d, J=8.1 Hz, 1H), 4.77 (s, 2H), 3.30 (s, 1H).

Intermediate 88(R)-4-(5-Bromo-2-methylbenzyl)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of (R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(2.261 g, 12.76 mmol) in acetonitrile (20 mL) was added4-bromo-2-(chloromethyl)-1-methylbenzene (2 g, 9.11 mmol) followed byaddition of DIPEA (4.77 mL, 27.3 mmol). The reaction mixture was stirredat 120° C. in a microwave reactor for 1 h. It was cooled, diluted withice water and extracted with EtOAc (2×20 mL). The combined organic layerwas washed with brine solution (30 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The crude residue was concentrated andpurified with silica gel chromatography to give the title compound (6 g,12.43 mmol, 136% yield) as a color less liquid. LCMS: m/z: 360.22(M+H)⁺, 2.17 min. (ret.time)

Intermediate 89(R)-2-Ethyl-4-(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of(R)-4-(5-bromo-2-methylbenzyl)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(3 g, 8.33 mmol) in 1,4-dioxane (10 mL) were addedbis(pinacolato)diboron (2.54 g, 9.99 mmol) and potassium acetate (1.634g, 16.65 mmol). The reaction mixture was degassed with argon for 10 minafter which PdCl₂(dppf)-CH₂Cl₂ adduct (0.680 g, 0.833 mmol) was added.The reaction mixture was heated at 90° C. for 16 h. The reaction mixturewas filtered though celite and washed with ethyl acetate (100 mL). Thefiltrate was concentrated. The crude product was purified with silicagel chromatography to give the title compound (2.8 g, 5.31 mmol, 63.8%yield) as a gum. LCMS: m/z: 408.42 (M+H)⁺, 2.17 min (ret.time)

The compounds in Table 4 were prepared by a method similar to the onedescribed for the preparation of9-Fluoro-2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepinehydrochloride. As is appreciated by those skilled in the art, theseanalogous examples may involve variations in general reactionconditions.

TABLE 4 Ret. Time Reagent Product Name Product Structure (M + H)⁺ (min)

2,2-Dimethyl-2,3,4,5- tetrahydropyrido[2,3- f][1,4]oxazepinehydrochloride

178.92 1.057

(R)-2-Ethyl-9-fluoro-2,3,4,5- tetrahydropyrido[3,4- f][1,4]oxazepine,Hydrochloride

197.0 4.11

8-Fluoro-2,2-dimethyl-2,3,4,5- tetrahydrobenzo[f][1,4]oxazepinehydrochloride

196.06 3.796

2,2,7-trimethyl-2,3,4,5- tetrahydrobenzo[f][1,4]oxazepine hydrochloride

192.27 1.32

Intermediate 90(R)-8-Chloro-2-ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepinehydrochloride

5-(Bromomethyl)-2,4-dichloropyridine

To a solution of (4,6-dichloropyridin-3-yl)methanol (7 g, 39.3 mmol) indichloromethane (100 mL) was added PBr₃ (7.42 mL, 79 mmol) at 0° C. andthe reaction stirred at ambient temperature for 2 h. The reactionmixture was evaporated under reduced pressure, quenched with saturatedNaHCO₃ solution (50 mL) and extracted with DCM (2×50 mL). The combinedorganic layer was washed with brine solution (40 mL) and dried overNa₂SO₄, filtered and concentrated to give the title compound (7 g, 22.54mmol, 57.3% yield). LCMS: m/z: 240.2 (M+2H)⁺, 2.43 min (ret. time)

(R)-1-(((4,6-Dichloropyridin-3-yl)methyl)amino)butan-2-ol

To a solution of (R)-1-aminobutan-2-ol (5.18 g, 58.1 mmol) indichloromethane (80 mL) was added 5-(bromomethyl)-2,4-dichloropyridine(7 g, 29.1 mmol) and TEA (8.10 mL, 58.1 mmol) and the reaction stirredfor 16 h at 25° C. The reaction mixture was diluted with water (40 mL)and extracted with DCM (3×30 mL). The combined organic layer was washedwith brine solution (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified by silica gelchromatography to give the title compound (5 g, 17.64 mmol, 60.7%yield). LC-MS: m/z 249.23 (M+H)⁺, 3.55 min (ret. time)

(R)-8-Chloro-2-ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine

To a solution of(R)-1-(((4,6-dichloropyridin-3-yl)methyl)amino)butan-2-ol (5 g, 20.07mmol) in dimethyl sulfoxide (50 mL) at 0° C. was added potassiumtert-butoxide (5.63 g, 50.2 mmol). The reaction mixture was heated to65° C. for 30 min. The reaction was quenched with ice water andextracted with ethyl acetate (3×50 mL). The combined organic layer waswashed with ice cold water (4×50 mL) then washed with brine (50 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified by silica gelchromatography to give the title compound (2 g, 8.52 mmol, 42.5% yield).LC-MS: m/z: 212.97 (M+H)⁺, 1.834 min (ret. time)

(R)-tert-Butyl8-chloro-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepine-4(5H)-carboxylate

To a solution of(R)-8-chloro-2-ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine (2 g,9.40 mmol) in dichloromethane (20 mL) was added TEA (1.966 mL, 14.11mmol) and Boc₂O (2.183 mL, 9.40 mmol) and the reaction stirred for 1 h.The reaction mixture was concentrated under reduced pressure. Thereaction was quenched with ice water and extracted with ethyl acetate(2×5 mL). The combined organic layer was washed with brine (5 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to give the crude residue. The crude product waspurified by silica gel chromatography to give the title compound (2 g,6.22 mmol, 66.1% yield). LC-MS: m/z: 313.04 (M+H)⁺, 5.76 min (ret. time)

(R)-8-Chloro-2-ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepinehydrochloride

To a solution of (R)-tert-butyl8-chloro-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepine-4(5H)-carboxylate(1.7 g, 5.43 mmol) in dioxane (20 mL) at 0° C. was added 4M HCl in1,4-Dioxnae (4.08 mL, 16.30 mmol). It was allowed to warm to 25° C. andthe reaction stirred for 3 h. The reaction mixture was concentrated. Tothe residue was added diethyl ether (20 mL) and the reaction stirred for30 min. The resulting solid was filtered and dried to give the titlecompound (1.4 g, 5.50 mmol, 101% yield) as white solid. LC-MS: 213.1(M−HCl)⁺, 3.877 min (ret. time)

Intermediate 91 4-Ethyl-6-fluoro-2,3,4,5-tetrahydro-1Hbenzo[c]azepinehydrochloride

2-(Bromomethyl)-3-fluorobenzonitrile

To a solution of 3-fluoro-2-methylbenzonitrile (1 g, 7.40 mmol) in CCl₄(10 ml, 104 mmol) was added AlBN (0.243 g, 1.480 mmol) and NBS (1.580 g,8.88 mmol). The reaction mixture was heated to reflux for 16 h. Thereaction mixture was quenched with water (20 mL), and extracted withethyl acetate (2×20 mL). The combined organic layer was washed withbrine (80 mL), dried over anhydrous Na₂SO₄, filtered and concentrated.The crude product was purified by silica gel chromatography using 5%ethyl acetate in n-hexane to give the title compound (500 mg, 2.336mmol, 31.6% yield). GC-MS m/z 213.0, 8.036 min (ret. time)

Ethyl 2-(2-cyano-6-fluorobenzyl)butanoate

To a solution of ethyl butyrate (271 mg, 2.336 mmol) intetrahydrofuran(10 mL) at −78° C. was added LDA (500 mg, 4.67 mmol) andthe reaction stirred for 45 min. Then a solution of2-(bromomethyl)-3-fluorobenzonitrile (500 mg, 2.336 mmol) intetrahydrofuran (4 mL) was added at same the temperature and thereaction stirred for 30 min. It was allowed to warm to 25° C. and thereaction stirred for 2 h. The reaction mixture was quenched with water(20 mL), and extracted with ethyl acetate (2×20 mL). The combinedorganic layer was washed with brine solution (80 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The crude product waspurified by silica gel chromatography using 5% ethyl acetate in n-Hexaneto give the title compound (400 mg, 0.742 mmol, 31.8% yield. LC-MS: m/z250.02 (M+H)⁺, 2.49 min (ret. time)

2-(2-(Aminomethyl)-6-fluorobenzyl)butan-1-ol

To a solution of ethyl 2-(2-cyano-6-fluorobenzyl)butanoate (400 mg,1.605 mmol) in tetrahydrofuran (5 mL) at 0° C. was added LAH (1.605 mL,1.605 mmol). The reaction was allowed to stir at 25° C. for 16 h. Thereaction mixture was quenched with saturated Na₂SO₄ solution (20 mL),and extracted with ethyl acetate (3×10 mL). The combined organic layerwas washed with brine solution (15 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give the title compound (320 mg, 0.905mmol, 56.4% yield). LC-MS: m/z 212.28 (M+H)⁺, 2.99 min (ret. time)

tert-Butyl 3-fluoro-2-(2-(hydroxymethyl)butyl)benzylcarbamate

To a solution of 2-(2-(aminomethyl)-6-fluorobenzyl)butan-1-ol (320 mg,1.515 mmol) in dichloromethane (10 mL) was added Boc₂O (0.352 mL, 1.515mmol) and the reaction stirred for 2 h at 25° C. The reaction mixturewas quenched with ice cold water and extracted with DCM (3×10 mL). Thecombined organic layer was washed with brine solution (15 mL), driedover anhydrous Na₂SO₄, filtered and concentrated. The crude residue waspurified by silica gel chromatography using 20% ethyl acetate inn-Hexane to give the title compound (300 mg, 0.809 mmol, 53.4% yield.GC-MS m/z 312.37(M+H)⁺, 5.50 min (ret. time)

2-(2-(((tert-Butoxycarbonyl)amino)methyl)-3-fluorobenzyl)butylmethanesulfonate

To a solution of tert-butyl2-fluoro-6-(2-(hydroxymethyl)butyl)benzylcarbamate (300 mg, 0.963 mmol)in dichloromethane (10 mL) was added TEA (0.269 mL, 1.927 mmol). Thereaction mixture was cooled to 0° C. then mesyl chloride (0.188 mL,2.409 mmol) was added and the reaction stirred for 1 h. The reactionmixture was quenched with ice cold water and extracted with DCM (3×20mL). The combined organic layer was washed with brine solution (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The cruderesidue was purified by silica gel chromatography using 15% ethylacetate in n-Hexane to give the title compound (280 mg, 0.591 mmol,61.3% yield). LC-MS: m/z 390.06(M+H)⁺, 2.56 min (ret. time)

tert-Butyl4-ethyl-6-fluoro-4,5-dihydro-1Hbenzo[c]azepine-2(3H)-carboxylate

To a solution of2-(2-(((tert-butoxycarbonyl)amino)methyl)-6-fluorobenzyl)butylmethanesulfonate (3.98 g, 10.22 mmol) in isopropanol (40 mL) was addedCs₂CO₃ (8.32 g, 25.5 mmol) and copper(I) iodide (0.195 g, 1.022 mmol).The reaction mixture was heated to 95° C. in a sealed tube for 16 h. Thereaction mixture was filtered through a celite pad, washed with ethylacetate (50 mL) and the filtrate was concentrated to give the cruderesidue. The crude product was purified by silica gel chromatographyusing 2% ethyl acetate in n-Hexane to give the title compound (2.5 g,7.96 mmol, 78% yield). LC-MS: m/z 294.29(M+H)⁺, 6.98 min (ret. time)

4-Ethyl-6-fluoro-2,3,4,5-tetrahydro-1Hbenzo[c]azepine hydrochloride

To a solution of tert-butyl4-ethyl-6-fluoro-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate (2.5g, 8.52 mmol) in 1,4-dioxane (5 mL) at 0° C. was added HCl in dioxane (4mL, 16.00 mmol, 4M). The reaction was stirred at 25° C. for 2 h. Thereaction mixture was concentrated to give the crude residue. Diethylether (20 ml) was added to the residue and the reaction stirred for 30min then filtered. The solid was dried under vacuum to give the titlecompound (1.5 g, 6.28 mmol, 73.7% yield) LC-MS m/z 194.0(M+H)⁺, 3.54 min(ret. time)

Intermediate 92 Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(3-oxo-2,3-dihydro-1H-inden-5-yl)propanoate

(3-((tert-Butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-5-yl)(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol

To a solution of 5-bromo-1,4-dimethyl-1H-benzo[d][1,2,3]triazole (3.60g, 15.92 mmol) in tetrahydrofuran (THF) (100 mL) was addedtert-butyllithium (13.47 mL, 17.51 mmol) at −78° C. under nitrogen. Thereaction mixture was stirred at −78° C. for 1 h, then3-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-indene-5-carbaldehyde(4.40 g, 15.92 mmol) in THF (20 mL) was slowly added. The reactionmixture was stirred at −78° C. for 2 h and ambient temperature for 8 h.The reaction mixture was quenched with saturated NH₄Cl solution andextracted with ethyl acetate (3×). The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified silica gel chromatography (petroleum ether:ethylacetate=1:1) to provide the title compound(3-((tert-Butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-5-yl)(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol(2.24 g, 11.76 mmol, 11.08% yield). LC/MS m/z 424.1 (M+H)⁺, 1.97 (ret.time).

Methyl3-(3-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To a solution of(3-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-5-yl)(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol(2 g, 4.72 mmol) in dry acetonitrile (40 mL), DBU (0.014 mL, 0.094 mmol)and 2,2,2-trichloroacetonitrile (0.818 g, 5.67 mmol) were added slowlyunder nitrogen at 25° C. The reaction mixture was stirred at 25° C. forhalf an hour after which((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (2.057 g, 11.80mmol) was added, followed by1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (0.066g, 0.236 mmol). The reaction mixture was stirred at 25° C. for 2 h afterwhich 40 mL of H₂O was added to quench the reaction and extracted withethyl acetate (3×). The combined organic layer was washed with brine andconcentrated. The residue was purified by silica gel chromatography(petroleum ether:ethyl acetate=4:1) to give the title compound methyl3-(3-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoateas a yellow solid. LC/MS m/z 508.2 (M+H)⁺, 2.52 (ret. time).

Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)-2,2-dimethylpropanoate

To a solution of methyl3-(3-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(1.1 g, 2.166 mmol) in tetrahydrofuran (THF) (15 mL) at 0° C., TBAF(0.623 g, 2.383 mmol) was added. The reaction mixture was stirred at 0°C. for 1 h after which the mixture was quenched with saturated NH₄Clsolution (20 mL) and extracted with ethyl acetate (3×). The combinedorganic layer was washed with water, brine, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography(petroleum ether:ethyl acetate=1:1) to provide the title compound methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)-2,2-dimethylpropanoate(650 mg, 1.487 mmol, 68.6% yield) as a yellow oil. LC/MS m/z 394.1(M+H)⁺, 1.88 (ret. time).

Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(3-oxo-2,3-dihydro-1H-inden-5-yl)propanoate

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)-2,2-dimethylpropanoate(650 mg, 1.652 mmol) in dichloromethane (DCM) (50 mL) was addedDess-Martin periodinane (1401 mg, 3.30 mmol) and one drop of water. Thereaction mixture was stirred at 25° C. for 8 h after which the mixturewas filtered and the filtrate was concentrated. The crude product waspurified by silica gel chromatography (petroleum ether:ethylacetate=1:1) to provide the title compound methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(3-oxo-2,3-dihydro-1H-inden-5-yl)propanoate(570 mg) as a yellow oil. LC/MS m/z 392.2 (M+H)⁺, 1.65 (ret. time).

Intermediate 93 (E)-Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)pent-2-enoate

(E)-Benzyl hept-2-en-6-ynoate

To a solution of3-((2-(dimethoxyphosphoryl)acetoxy)methyl)benzene-1-ylium (51.7 g, 201mmol) in tetrahydrofuran (THF) (150 mL) was added sodium hydride (8.04g, 201 mmol)) in small portions at 0° C. After it was stirred for 35min, pent-4-ynal (15.0 g, 183 mmol) was added slowly. The reactionmixture was stirred at 0° C. for 50 min. 100 mL of saturated NH₄Cl wasadded and the solution was extracted with DCM (2×). The combined organiclayer was washed with brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel chromatography (petroleum ether:ethylacetate=50:1) to give the desired product (E)-benzyl hept-2-en-6-ynoate(12.0 g, 56.0 mmol, 30.7% yield) as an oil. LC/MS m/z 215.1 (M+H)⁺, 2.00(ret. time).

(E)-Benzyl 5-(1-ethyl-1H-1,2,3-triazol-4-yl)pent-2-enoate

To a solution of (E)-benzyl hept-2-en-6-ynoate (10.0 g, 46.7 mmol) intetrahydrofuran (THF) (200.0 mL) and water (200.0 mL), sodium azide(9.10 g, 140 mmol), iodoethane (21.84 g, 140 mmol), copper(I) iodide(1.778 g, 9.33 mmol) and NaHCO₃ (11.76 g, 140 mmol) were added slowlyunder nitrogen. The reaction mixture was stirred at 70° C. for 16 h. Thereaction mixture was extracted with ethyl acetate (3×). The combinedorganic layer was concentrated. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=10:1) to provide the titlecompound (E)-benzyl 5-(1-ethyl-1H-1,2,3-triazol-4-yl)pent-2-enoate (7.5g, 24.97 mmol, 53.5% yield). LC/MS m/z 286.2 (M+H)⁺, 1.78 (ret. time).

Intermediate 94 (S)-Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(R)-Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

3-Chloro-N-ethyl-2-nitroaniline

1-Chloro-3-fluoro-2-nitrobenzene (25 g, 142 mmol) in ethanamine (200 ml,1198 mmol) was stirred at 40° C. for 16 h after which 300 mL of waterwas added and the mixture extracted with ethyl acetate (3×). Thecombined organic layer was dried over Na₂SO₄ and concentrated to providethe title compound 3-chloro-N-ethyl-2-nitroaniline (30 g, 139 mmol, 98%yield) which was carried to the next step without further purification.LC/MS m/z 201.1 (M+H)⁺, 2.06 (ret. time).

4-Bromo-3-chloro-N-ethyl-2-nitroaniline

To a solution of 3-chloro-N-ethyl-2-nitroaniline (30 g, 150 mmol) inN,N-dimethylformamide (DMF) (200 mL), NBS (26.6 g, 150 mmol) inN,N-dimethylformamide (DMF) (200 mL) was added at 0° C. under nitrogen.The reaction mixture was stirred at 0° C. for 1 h and quenched with icewater under vigorous stirring. The solid was filtered to provide thetitle compound 4-bromo-3-chloro-N-ethyl-2-nitroaniline (40 g, 139 mmol,93% yield). LC/MS m/z 278.9 (M+H)⁺, 1.91 (ret. time).

4-Bromo-3-chloro-N1-ethylbenzene-1,2-diamine

To a solution of 4-bromo-3-chloro-N-ethyl-2-nitroaniline (40 g, 143mmol) in ethanol (200 mL), 1,2-Dichloroethane (DCE) (200 mL) and nickel(8.40 g, 143 mmol) were added slowly under nitrogen at 0° C. after whichhydrazine (8.42 mL, 172 mmol) was added dropwise. The reaction mixturewas stirred at 0° C. for 0.5 h. The solid was filtered, 200 mL of waterwas added to the solid and extracted with ethyl acetate (3×). Thecombined organic phase was concentrated to provide the title compound4-bromo-3-chloro-N1-ethylbenzene-1,2-diamine (35 g, 126 mmol, 88% yield)which was carried to the next step without further purification. LC/MSm/z 249.0 (M+H)⁺, 1.97 (ret. time).

5-Bromo-4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazole

A stirred suspension of 4-bromo-3-chloro-N1-ethylbenzene-1,2-diamine (35g, 140 mmol) in a solution of sulfuric acid (29.9 ml, 561 mmol) in water(300 mL) was treated with a solution of sodium nitrite (14.52 g, 210mmol) in water (300 mL). The reaction mixture was stirred at 0° C. for 1h after which the solid was filtered to provide the title compound5-bromo-4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazole (30 g, 104 mmol,73.9% yield). LC/MS m/z 260.0 (M+H)⁺, 1.89 (ret. time).

(E)-Benzyl 3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate

A mixture of 5-bromo-4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazole (10 g,38.4 mmol), benzyl acrylate (8.09 g, 49.9 mmol),1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (3.13 g, 3.84 mmol) and triethylamine (16.05 mL,115.0 mmol) in N,N-dimethylformamide (DMF) (100 mL) was stirred at 115°C. for 12 h. Water (100 mL) was added and the mixture extracted withethyl acetate (3×). The combined organic layer was concentrated and theresidue was purified by silica gel chromatography (petroleum ether:ethylacetate=3:1) to provide the title compound (E)-benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (7.0 g,18.43 mmol, 48.0% yield). LC/MS m/z 342.1 (M+H)+, 2.01 (ret. time).

Benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

To a solution of (E)-benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (7 g, 20.48mmol) in 1,4-dioxane (80 mL) and water (40 mL) was added(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(12.70 g, 51.2 mmol) and TEA (7.14 mL, 51.2 mmol). After it was stirredfor 5 min, chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.505 g, 1.024mmol) was added. The reaction mixture was stirred at 90° C. for 16 h.After it was cooled to ambient temperature, it was extracted with EtOAc(3×). The combined organic layer was concentrated and purified by silicagel chromatography (petroleum ether:ethyl acetate=5:4) to provide thetitle compound benzyl 3-(4-chloro-1-ethyl-1H-benzo[d][1, 2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (10 g,18.32 mmol, 89% yield). LC/MS m/z 464.1 (M+H)⁺, 1.72 (ret. time).

(S)-Benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoateand (R)-Benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

Benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(10 g, 21.55 mmol) was separated by Chiral SFC (Column: AD IC 20×250 mm;Co-solvent: CO₂/MEOH (0.2% methanol amina)=50/50; Flowrate: 130 g/min;Back pressure: 100 Bar) to give single enantiomerically pure (S)-benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(3.6 g, 7.45 mmol, 34.6% yield) (chiral SFC ret. time: 1.97 min) andenantiomerically pure (R)-benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(3.5 g, 7.39 mmol, 34.3% yield) (chiral SFC ret. time: 8.13 min).

(S)-Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of (S)-benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(3.6 g, 7.76 mmol) in dichloromethane (DCM) (50 mL), imidazole (0.792 g,11.64 mmol) and tert-butylchlorodimethylsilane (1.754 g, 11.64 mmol)were added at 0° C. The reaction mixture was stirred at 10° C. for 2 h.The solvent was removed and the residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=3:1) to provide the titlecompound (S)-benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(3.5 g, 5.93 mmol, 76% yield) as a yellow oil. LC/MS m/z 578.3 (M+H)⁺,2.488 (ret. time).

(R)-Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of (R)-benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(3.5 g, 7.54 mmol) in dichloromethane (DCM) (50 mL), imidazole (0.565 g,8.30 mmol) and tert-butylchlorodimethylsilane (1.364 g, 9.05 mmol) wereadded at 00° C. The reaction mixture was stirred at 0° C. to 10° C. for2 h after which the solvent was removed and the residue was purifiedsilica gel chromatography (petroleum ether:ethyl acetate=3:1) providethe title compound (R)-benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(3.3 g, 5.59 mmol, 74.1% yield) as a yellow oil. LC/MS m/z 578.3 (M+H)⁺,2.47 (ret. time).

Intermediate 95 1-((1H-imidazol-2-yl)methyl)azepane

Azepane N33442-33-A1

The mixture of azepan-2-one (8.0 g, 70.7 mmol) and LiAlH₄ (5.37 g, 141mmol) in tetrahydrofuran (THF) (50 mL) was stirred at ice bath for 8 hunder nitrogen after which 5.3 mL of water, 5.3 mL of 10% NaOH aqueoussolution and 16 mL of water were added dropwise, respectively. The solidwas filtered. The filtrate was concentrated to provide the titlecompound azepane (3.0 g, 30.2 mmol, 42.8% yield) as an oil which wascarried to the next step without further purification. LC/MS m/z 100.2(M+H)⁺, 0.48 (ret. time).

1-((1H-imidazol-2-yl)methyl)azepane

To a solution of azepane (2.0 g, 20.17 mmol) in 1,2-dichloroethane (DCE)(120 mL), acetic acid (1 mL, 17.47 mmol), 1H-imidazole-2-carbaldehyde(1.938 g, 20.17 mmol) and NaBH(OAc)₃ (17.10 g, 81 mmol) were added at 0°C. The reaction mixture was stirred at 25° C. for 16 h. The mixture wasquenched with aqueous NaHCO₃ (100 mL) and extracted with DCM (2×), theorganic layer was washed with water (2×), brine, dried over Na₂SO₄ andconcentrated. The residue was purified by reverse phase preparative HPLC(MeOH/0.05% NH₃H₂O/H₂O=50%) to provide the title compound1-((1H-imidazol-2-yl)methyl)azepane (1.5 g, 7.95 mmol, 39.4% yield) as asolid. LC/MS m/z 180.2 (M+H)⁺, 1.37 (ret. time).

Intermediate 96 1-((1H-Imidazol-2-yl)methyl)-4-ethylpiperidine

tert-Butyl 4-ethylidenepiperidine-1-carboxylate

Ethyltriphenylphosphonium bromide (27.9 g, 75 mmol) was added to theLiHMDS (75 mL, 75 mmol) in THF (60 mL) at 0° C. After the reactionmixture was stirred at 00° C. for 1 h, a solution of tert-butyl4-oxopiperidine-1-carboxylate (10.0 g, 50.2 mmol) in tetrahydrofuran(THF) (60 mL) was added and stirred for a further 2 h at ambienttemperature. Brine was added to quench the reaction and extracted withethyl acetate (2×). The combined organic layer was washed with brine andconcentrated. The residue was purified by silica gel chromatography(petroleum ether:ethyl acetate=10:1) to give the title compoundtert-butyl 4-ethylidenepiperidine-1-carboxylate (6.2 g, 29.3 mmol, 58.5%yield) as an oil. LC/MS m/z 156.2 (M+H-56)⁺, 2.21 min (ret. time)

tert-Butyl-4-ethylpiperidine-1-carboxylate

The mixture of tert-butyl 4-ethylidenepiperidine-1-carboxylate (6200 mg,29.3 mmol) and Pd/C (10%, 1561 mg, 14.67 mmol) in methanol (100 mL) washydrogenated with H₂ ballloon for 5 h. The mixture was filtered throughcelite and the organic layer was concentrated to give the title compoundtert-butyl 4-ethylpiperidine-1-carboxylate (6200 mg, 29.1 mmol, 99%yield) as an oil. LC-MS m/z 158.1 (M+H)⁺, 2.28 min (ret. time)

4-Ethylpiperidine

The mixture of tert-butyl 4-ethylpiperidine-1-carboxylate (6200 mg, 29.1mmol), trifluoroacetic acid (2.239 mL, 29.1 mmol) in dichloromethane(DCM) (50 mL) was stirred at ambient temperature for 5 h. The solventwas concentrated to give the title compound 4-ethylpiperidine (2500 mg,22.08 mmol, 76% yield) as an oil which was carried to the next stepwithout further purification. LC/MS m/z 114.2 (M+H)⁺, 1.03 min (ret.time)

1-((1H-Imidazol-2-yl)methyl)-4-ethylpiperidine

To a mixture of 4-ethylpiperidine (1200 mg, 10.60 mmol) and1H-imidazole-2-carbaldehyde (1019 mg, 10.60 mmol) was added titanium(IV)isopropoxide (3.73 mL, 12.72 mmol) dropwise. After it was stirred at 25°C. for 2 h, ethanol (120 mL) and NaCNBH₃ (666 mg, 10.60 mmol) were addedand stirred for another 8 h. Water (2 mL) was added and the solvent wasconcentrated. The residue was purified by reverse-phase HPLC (MeOH/0.05%NH₃H₂O/H₂O=50%) to give the title compound1-((1H-imidazol-2-yl)methyl)-4-ethylpiperidine (850 mg, 4.18 mmol, 39.4%yield) as a solid. LC-MS m/z 194.2 (M+H)⁺, 1.53 min (ret. time)

Intermediate 97 4-Fluoro-3-(((4-methoxybenzyl)oxy)methyl)benzaldehyde

(5-Bromo-2-fluorophenyl)methanol

Trimethyl borate (2.55 mL, 22.83 mmol) was added to a stirred solutionof 5-bromo-2-fluorobenzoic acid (5.0 g, 22.83 mmol) in tetrahydrofuran(THF) (60 mL) under argon and the mixture was stirred at ambienttemperature. After 15 minutes, a solution of DMS (21.69 mL, 43.4 mmol)was added to the reaction mixture at 0° C. and stirred at ambienttemperature for 16 h. Methanol (10 mL) was added slowly to the reactionmixture. After 30 min, the solvent was evaporated and ethyl acetate wasadded to the residue. The organic layer was washed with aqueous sodiumbicarbonate solution and water, dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel chromatography (petroleum ether:ethylacetate=4:1) to give title compound (5-bromo-2-fluorophenyl)methanol(4.65 g, 19.07 mmol, 84% yield) as a white solid. LC/MS m/z 189.1(M+H)⁺, 1.52 (ret. time).

4-Bromo-1-fluoro-2-(((4-methoxybenzyl)oxy)methyl)benzene

To a solution of (5-bromo-2-fluorophenyl)methanol (9.25 g, 45.1 mmol) inN,N-dimethylformamide (DMF) (80 mL) at 0° C. under nitrogen, sodiumhydride (2.165 g, 54.1 mmol) was added in two portions. The reactionmixture was stirred at 0° C. for 20 min after which1-(chloromethyl)-4-methoxybenzene (8.48 g, 54.1 mmol) was added to themixture and it was stirred at 0° C. to 25° C. for 1 hr. Then ice waterwas added to the reaction mixture under 0° C. The reaction mixture wasextracted with ethyl acetate (3×). The combined organic layer was washedwith brine and dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified with silica gel chromatography (petroleum ether:ethylacetate=5:1) to give the title compound4-bromo-1-fluoro-2-(((4-methoxybenzyl)oxy)methyl)benzene (13.25 g, 40.7mmol, 90% yield) as an oil. LC/MS m/z 325.1/326.1 (M+H)⁺, 1.46 (ret.time).

4-Fluoro-3-(((4-methoxybenzyl)oxy)methyl)benzaldehyde

To a solution of4-bromo-1-fluoro-2-(((4-methoxybenzyl)oxy)methyl)benzene (13.25 g, 40.7mmol) in tetrahydrofuran (THF) (100 mL) at −78° C. under N₂,n-butyllithium (19.56 mL, 48.9 mmol) was carefully added. The reactionmixture was stirred at −78° C. for 45 min. DMF (15.78 mL, 204 mmol) wasadded. The reaction mixture was stirred at −78° C. to 25° C. for another30 min. The reaction mixture was quenched with saturated NH₄Cl andextracted with ethyl acetate (3×). The organic layer was washed withwater (2×), brine (2×), dried over Na₂SO₄ and concentrated. The residuewas purified with silica gel chromatography (petroleum ether:ethylacetate=1:10) to give the title compound4-fluoro-3-(((4-methoxybenzyl)oxy)methyl)benzaldehyde (10.5 g, 37.8mmol, 93% yield) as an oil. LC/MS m/z 296.9 (M+Na)⁺, 2.03 (ret. time).

Example 13-(3-((2,3-Dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, trifluoroacetic acid salt

A mixture of ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(80 mg, 0.207 mmol), 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (55.7 mg,0.373 mmol) and DIEA (0.109 mL, 0.622 mmol) in tetrahydrofuran (THF)(1.5 mL) was heated in a Biotage microwave at high absorption for 2 h at120° C. The reaction mixture was concentrated and the resulting mixturere-dissolved in methanol (2 mL), 2 M LiOH (0.622 mL, 1.244 mmol) wasadded. It was heated at 85° C. for 30 min. 0.8 mL of 1N HCl and 1.5 mLof DMSO were added, solvents removed, and the sample was purified byreverse-phase HPLC (with 0.1% TFA condition) to give the title compound(107 mg, 0.227 mmol, 110% yield) as white solid. LC-MS: m/z 471.5(M+H)⁺, 0.66 min (ret. time).

Example 23-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, trifluoroacetic acid salt

A mixture of ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(70 mg, 0.181 mmol), 2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(57.9 mg, 0.327 mmol), and DIEA (0.095 mL, 0.544 mmol) intetrahydrofuran (THF) (3 mL) was heated in a Biotage microwave at highabsorption for 2 h at 120° C. The reaction mixture was concentrated andre-dissolved in methanol (2 mL). It was heated at 85° C. for 30 min. 0.8mL of 1N HCl and 1.5 mL of DMSO were added, solvents removed, and thesample was purified by reverse-phase HPLC (with 0.1% TFA condition) togive the title compound (86.68 mg, 0.174 mmol, 96% yield) as whitesolid. LC-MS m/z 499.5 (M+H)⁺, 0.85 min (ret. time).

Example 3 Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoate,trifluoroacetic acid salt

2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of LAH (119 mg, 3.14 mmol) in tetrahydrofuran (THF) (2 mL)was added a solution of 2-methylbenzo[f][1,4]oxazepine-3,5(2H,4H)-dione(200 mg, 1.046 mmol) in tetrahydrofuran (THF) (2 mL). The mixture washeated in a Biotage microwave at high absorption for 2 h at 120° C. Tothe reaction mixture was added 0.52 mL saturated Na₂SO₄. The mixture wasstirred for 30 min. The reaction mixture turns from grey to whitesolution. Solid was filtered and washed with ethyl acetate. The filtratewas concentrated to give the title compound (179.5 mg, 1.100 mmol, 105%yield) as oil. LC-MS m/z 163.9 (M+H)+, 0.42 min (ret. time).

Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoate,trifluoroacetic acid salt

To a solution of3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(0.130 mL, 0.302 mmol) and2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (89 mg, 0.544 mmol) intetrahydrofuran (THF) (3 mL) at ambient temperature was addedN,N-diisopropylethylamine (DIEA) (0.158 mL, 0.906 mmol). The reactionmixture was heated in a Biotage microwave at high absorption for 2 hr at180° C. After cooling, the reaction mixture was concentrated to removesolvent. The crude product was redissolved in methanol (3 mL). To thereaction mixture was added 2 M lithium hydroxide (0.453 mL, 0.906 mmol).The reaction mixture was heated in a Biotage microwave at highabsorption for 30 min at 80° C. After cooling, 1 N HCl (0.8 mL) and DMSO(2 mL) was added and the volatiles removed. The crude product waspurified via reverse-phase HPLC under acidic conditions to give thetitle compound3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid, trifluoroacetic acid salt (41.3 mg, 0.085 mmol, 28.2% yield).LC-MS m/z 485.5 (M+H)⁺, 0.72 min (ret. time). ¹H NMR (400 MHz, DMSO-d₆)b ppm 1.30 (d, J=6.27 Hz, 3H) 2.27 (br. s., 1H) 2.36 (br. s., 2H) 2.79(s, 3H) 3.01-3.21 (m, 2H) 3.27-3.46 (m, 1H) 3.53 (br. s., 1H) 4.12 (br.s., 1H) 4.25 (s, 3H) 4.34-4.64 (m, 4H) 4.82-4.91 (m, 1H) 7.07-7.63 (m,9H) 9.93 (br. s., 1H)

Example 45-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)pentanoicacid, trifluoroacetic acid salt

(2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol

To a solution of (5-bromo-2-methylphenyl)methanol (49 g, 244 mmol) in1,4-dioxane (600 mL) was added potassium acetate (59.8 g, 609 mmol) andbis(pinacolato)diboron (80 g, 317 mmol). The reaction mixture wasdegassed with Argon for 30 min after which PdCl₂(dppf)-CH₂Cl₂ adduct(19.90 g, 24.37 mmol) was added to reaction mixture and stirred at 100°C. for 16 h. After completion, the reaction mixture was cooled andfiltered through celite. The filtrate was concentrated and the cruderesidue was purified via silica gel chromatography to give the titlecompound (40 g, 159 mmol, 65.2% yield) as white solid. LC-MS m/z 248.1(M+H)⁺, 3.71 min (ret. time).

Ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)pentanoate

To a suspension of (E)-ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)pent-2-enoate (500 mg, 2.239 mmol),(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(667 mg, 2.69 mmol), and [RhCl(cod)]₂ (110 mg, 0.224 mmol) in1,4-dioxane (2 mL) and water (1 mL) at ambient temperature was addedtriethylamine (0.936 mL, 6.72 mmol). The resulting suspension was heatedat 90° C. for 1 h. The reaction mixture was passed through celite andwashed with EtOAc. The organic layer was collected and concentrated togive the crude product which was purified via silica gel chromatographyto give the title compound (685 mg, 1.983 mmol, 89% yield) as oil.LC/MS: m/z 346.1 (M+H)⁺, Rt 0.83 min.

Ethyl3-(3-(chloromethyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate

To a solution of ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)pentanoate(95 mg, 0.275 mmol) in dichloromethane (DCM) (2 mL) was added SOCl₂(0.040 mL, 0.550 mmol). The result reaction mixture was stirred atambient temperature for 40 min. Solvent was evaporated to afford thetitle compound (95 mg, 0.261 mmol, 95% yield). LC/MS: m/z 364.4 (M+H)⁺,Rt 1.01 min.

5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)pentanoicacid, trifluoroacetic acid salt

A mixture of ethyl3-(3-(chloromethyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate(95 mg, 0.261 mmol), 2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(83 mg, 0.470 mmol) and DIEA (0.137 mL, 0.783 mmol) in tetrahydrofuran(THF) (3 mL) was heated via microwave for 2 h at 120° C. The solvent wasremoved and the crude residue re-dissolved in methanol (2 mL). It washeated in a Biotage microwave at high absorption at 80° C. for 35 min.LC-MS showed the reaction was not complete. It was heated in a Biotagemicrowave at high absorption at 80° C. for 30 min. 0.8 mL of 1 N HCl and1.5 mL of DMSO were added. The mixture was concentrated and purifiedwith reverse-phase HPLC to give title compound (132 mg, 0.277 mmol, 106%yield). LC-MS m/z 477.1 (M+H)⁺, 0.79 min (ret. time).

Example 5(3S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, trifluoroacetic acid salt

2-Ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a suspension of LAH (294 mg, 7.75 mmol) in tetrahydrofuran (THF) (2mL) was added a solution of2-ethylbenzo[f][1,4]oxazepine-3,5(2H,4H)-dione (530 mg, 2.58 mmol) intetrahydrofuran (THF) (2 mL). The mixture was heated via microwave for 2h at 120° C. after which time 4.8 mL saturated Na₂SO₄ was added dropwise. The mixture was stirred for 30 min, the solid was filtered andwashed with ethyl acetate. The filtrate was concentrated to give thetitle compound (450 mg, 98%) as an oil. LC-MS m/z 178.1 (M+H)⁺, 0.58 min(ret. time).

(3S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, trifluoroacetic acid salt

A mixture of (S)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(80 mg, 0.207 mmol), 2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(55.1 mg, 0.311 mmol), and DIEA (0.109 mL, 0.622 mmol) intetrahydrofuran (THF) (3 mL) was heated via microwave for 2 h at 120° C.The solvent was removed and the resulting residue re-dissolved inmethanol (2 mL). The reaction mixutre was heated at 85° C. for 30 minafter which 0.8 mL of 1 N HCl and 1.5 mL of DMSO were added. Mostsolvents were dried and purified with reverse-phase HPLC to give thetitle compound (78.8 mg, 0.129 mmol, 62.0% yield) as white solid. LC-MSm/z 499.5 (M+H)⁺, 0.85 min (ret. time).

Example 6(3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, trifluoroacetic acid salt

A mixture of (R)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(90 mg, 0.233 mmol), 2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(62.0 mg, 0.350 mmol), and DIEA (0.122 mL, 0.700 mmol) intetrahydrofuran (THF) (3 mL) was heated via microwave for 2 h at 120° C.The solvent was removed and the residue re-dissolved in methanol (2 mL).The reaction mixture was heated at 85° C. for 30 min. after which time0.8 mL of 1 N HCl and 1.5 mL of DMSO were added. Volatile solvents wereremoved and the crude product purified with reverse-phase HPLC to givethe title compound (67.9 mg, 0.111 mmol, 47.5% yield) as white solid.LC-MS m/z 499.5 (M+H)⁺, 0.85 min (ret. time).

Example 73-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((8-methoxy-4-methyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoicacid

Methyl 3-(3-methoxyphenyl)propanoate

To a solution of 3-(3-methoxyphenyl)propanoic acid (5000 mg, 27.7 mmol)in methanol (50 mL), SOCl₂ (2.025 mL, 27.7 mmol) was added slowly undernitrogen at ambient temperature. The reaction mixture was stirred at 65°C. for 12 hrs then concentrated under a stream of nitrogen at 50° C.Ethyl acetate (100 mL) was added and the organic phase washed withaqueous NaHCO₃, dried with MgSO₄ and concentrated to afford the titlecompound methyl 3-(3-methoxyphenyl)propanoate (5.4 g, 26.7 mmol, 96%yield). LC-MS m/z 195.1 (M+H)⁺, 1.67 (ret. time).

3-(3-Methoxyphenyl)propan-1-ol

To a solution of methyl 3-(3-methoxyphenyl)propanoate (5 g, 25.7 mmol)in tetrahydrofuran (50 mL), was added LiAlH₄ (1.172 g, 30.9 mmol) slowlyunder nitrogen at 25° C. The reaction mixture was stirred at 25° C. for16 hrs and was cooled to 0° C. after which 1.17 mL of water was added,followed by 1.17 mL of 10% NaOH, and 3.5 mL of water. The solid wasfiltered and the filtrate was concentrated under a stream of nitrogen at50° C. to afford the title compound 3-(3-methoxyphenyl)propan-1-ol (4.1g, 23.19 mmol, 90% yield). LC-MS m/z 167.2 (M+H)⁺, 1.45 (ret. time).

3-(3-Methoxyphenyl)propanal

To a solution of 3-(3-methoxyphenyl)propan-1-ol (3500 mg, 21.06 mmol) indichloromethane (DCM) (50 mL) at 30° C. was added PCC (19.500 g, 90mmol) slowly under nitrogen. The reaction mixture was stirred at 30° C.for 12 h. Water (50 mL) was added to reaction mixture and the mixtureextracted with ethyl acetate (3×60 mL) The combined organic layer wasdried with MgSO₄, filtered and concentrated. The crude product waspurified by silica gel column (hexane:ethyl acetate=20:1) to afford thetitle compound 3-(3-methoxyphenyl)propanal (2000 mg, 10.35 mmol, 49.2%yield). LC-MS m/z 165.0 (M+H)+1.09 (ret. time).

(S,E)-2-(Methoxymethyl)-N-(3-(3-methoxyphenyl)propylidene)pyrrolidin-1-amine

To a solution of 3-(3-methoxyphenyl)propanal (1187 mg, 6.14 mmol) indichloromethane (DCM) (20 mL) at 30° C. was added(S)-2-(methoxymethyl)pyrrolidin-1-amine (800 mg, 6.14 mmol) and MgSO₄(740 mg, 6.14 mmol) slowly under nitrogen. The reaction mixture wasstirred at 30° C. for 12 h. The mixture was filtered and the filtratewas concentrated. The crude product was purified by silica gel column(hexane:ethyl acetate=4:1) to afford the title compound(S,E)-2-(methoxymethyl)-N-(3-(3-methoxyphenyl)propylidene)pyrrolidin-1-amine(1700 mg, 5.54 mmol, 90% yield). LC-MS m/z 277.2 (M+H)⁺, 1.50 (ret.time).

(2S,E)-2-(Methoxymethyl)-N-(3-(3-methoxyphenyl)-2-methylpropylidene)pyrrolidin-1-amine

To a solution of(S,E)-2-(methoxymethyl)-N-(3-(3-methoxyphenyl)propylidene)pyrrolidin-1-amine(800 mg, 2.89 mmol) in tetrahydrofuran (THF) (20 mL) at −78° C. wasadded 2 M LDA in THF (7.24 mL, 14.47 mmol) slowly under nitrogen. Thereaction mixture was stirred at −78° C. for 30 mins then warmed to 0° C.and stirred at 0° C. for 1 h. It was cooled to −78° C., a solution ofiodomethane (1.086 mL, 17.37 mmol) in 5 mL THF was added dropwise. Thereaction mixture was stirred at −78° C. for 1 h, then it was slowlywarmed to ambient temperature and stirred for 12 h. Water (50 mL) wasadded and the mixture extracted with ethyl acetate (3×50 mL). Thecombined organic layer was dried with MgSO₄, filtered and concentrated.The crude product was purified by preparative HPLC to afford the titlecompound(2S,E)-2-(methoxymethyl)-N-(3-(3-methoxyphenyl)-2-methylpropylidene)pyrrolidin-1-amine(650 mg, 2.126 mmol, 73.5% yield). LC-MS m/z 291.2 (M+H)⁺, 1.54 (ret.time).

(2S)-2-(Methoxymethyl)-N-(3-(3-methoxyphenyl)-2-methylpropyl)pyrrolidin-1-amine

To a solution of(2S,E)-2-(methoxymethyl)-N-(3-(3-methoxyphenyl)-2-methylpropylidene)pyrrolidin-1-amine(1.5 g, 5.17 mmol) in tetrahydrofuran (THF) (10 mL) at ambienttemperature was added 1M LiAlH₄ in THF (12.91 mL, 12.91 mmol) slowlyunder nitrogen. The reaction mixture was stirred at 65° C. for 10 h. 1 NNaOH (5 mL) was added and the mixture was extracted with ethyl acetate(3×10 mL). The combined organic layer was washed with brine, dried withMgSO₄, filtered and concentrated to afford the title compound(2S)-2-(methoxymethyl)-N-(3-(3-methoxyphenyl)-2-methylpropyl)pyrrolidin-1-amine(1.5 g, 4.10 mmol, 79% yield). LC-MS m/z 293.2 (M+H)⁺, 1.63 (ret. time).

7-Methoxy-4-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine

To a solution of7-methoxy-2-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-4-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine(670 mg, 2.201 mmol) in tetrahydrofuran (THF) (10 mL) at ambienttemperature was added 1 M BH₃ in THF (1.642 ml, 1.642 mmol) slowly undernitrogen. The reaction mixture was stirred at 60° C. for 48 h. After itwas cooled to ambient temperature, 20 mL of 4 N NaOH was added slowly.It was heated at 60° C. for 4 h, 10 mL of water was added and themixture extracted with ethyl acetate (3×50 mL). The combined organiclayers were dried with MgSO₄, filtered and concentrated to afford thetitle compound 7-methoxy-4-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine(340 mg, 0.729 mmol, 33.1% yield). LC-MS m/z 192.1 (M+H)⁺, 0.88 (ret.time).

Ethyl3-(3-(bromomethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(500 mg, 1.361 mmol) in dichloromethane (DCM) (5 mL) at 0° C. undernitrogen was added a solution of PBr₃ (0.513 ml, 5.44 mmol) indichloromethane (DCM) (5 mL) slowly. The reaction mixture was stirred at0° C. for 30 mins after which 10 mL of water was added and the mixtureextracted with ethyl acetate (3×10 mL). The combined organic layers weredried with MgSO₄, filtered and concentrated. The crude product waspurified by preparative HPLC to afford ethyl3-(3-(bromomethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(320 mg, 0.639 mmol, 47.0% yield). LC-MS m/z 432.0 (M+H)⁺, 1.26 (ret.time).

Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((7-methoxy-4-methyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoate

To a mixture of 7-methoxy-4-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine(340 mg, 0.711 mmol) and ethyl3-(3-(bromomethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(200 mg, 0.465 mmol) in dichloromethane (DCM) (10 mL) was added DIPEA(0.081 mL, 0.465 mmol) under nitrogen at ambient temperature. Thereaction mixture was stirred at ambient temperature for 16 hrs afterwhich the reaction mixture was concentracted and purified by preparativeHPLC to afford the title compound ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((7-methoxy-4-methyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoate(230 mg, 0.408 mmol, 88% yield). LC-MS m/z 541.3 (M+H)⁺, 1.07 (ret.time).

3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((7-methoxy-4-methyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoicacid

To a solution of ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((7-methoxy-4-methyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoate(230 mg, 0.425 mmol) in tetrahydrofuran (THF) (5 mL) at 25° C. undernitrogen was added a solution of lithium hydroxide (40.7 mg, 1.702 mmol)in water (5.00 mL) slowly. The reaction mixture was stirred at 25° C.for 16 h. 1N HCl was added to pH=3. The mixture was extracted with ethylacetate (3×20 mL) and the combined organic layers were dried with MgSO₄,filtered and concentrated. The crude product was recrystallized fromethyl acetate and hexane to afford the title compound3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((7-methoxy-4-methyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoicacid (100 mg, 0.195 mmol, 45.9% yield). LC-MS m/z 513.1 (M+H)⁺, 1.67(ret. time).

Example 83-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, formic acid salt

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(50 mg, 0.131 mmol) in dichloromethane (0.2 mL) was added thionylchloride (0.019 mL, 0.262 mmol). The resulting reaction mixture wasstirred at ambient temperature for 100 min after which time it wasevaporated under vacuum then dissolved in acetonitrile (1.5 mL).2,2-Dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine, hydrochloride(42.0 mg, 0.197 mmol), K₂CO₃ (54.3 mg, 0.393 mmol) and sodium iodide(3.93 mg, 0.026 mmol) were added. The resulting reaction mixture wasstirred at 40° C. for 18 h. This reaction mixture was concentrated. Itwas dissolved in methanol (1.5 mL) and NaOH (3 N) (0.218 mL, 0.655 mmol)was added. The resulting reaction mixture was heated with microwave at80° C. for 20 min. It was heated again with microwave at 100° C. for 20min; heated again with microwave at 120° C. for 30 min; heated againwith microwave at 130° C. for 90 min. The reaction mixture was acidifiedwith HCl (3 N) to pH ˜6, evaporated under vacuum, purified by reversephase HPLC to afford desired product3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, formic acid salt (50.9 mg, 0.091 mmol, 69.5% yield). LC-MS m/z527.4 (M+H)⁺, 0.83 min (ret. time).

Example 9 Ammonium3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

A mixture of ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(0.039 g, 0.1 mmol), 3-(1H-pyrazol-1-yl)piperidine (0.023 g, 0.15 mmol)and N,N-diisopropylethylamine (0.07 mL, 0.4 mmol) inN,N-dimethylformamide (DMF) (0.6 mL) was heated to 70° C. for 18 h. Thecooled reaction mixture was evaporated, redissolved in acetonitrile (0.5mL) and ethanol (0.15 mL). Sodium hydroxide (10 M, 0.1 mL) added. Thesolution was stirred at 40° C. for 18 h. The cooled reaction mixture wasevaporated, redissolved in DMSO:MeOH (1:1, 1 mL) and the residuepurified by MDAP using a high pH ammonium carbonate buffer (pH 10) togive the title compound ammonium3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(36.6 mg, 69.7% yield). LC-MS m/z 473.2 (M+H)⁺, 0.67 min (ret. Time)

Example 10 Ammonium3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-(5-isopropyl-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)methyl)-4-methylphenyl)propanoate

A mixture of ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(0.0347 g, 0.09 mmol), 3-isopropyl-5-(pyrrolidin-2-yl)-4H-1,2,4-triazole(0.0258 g, 0.135 mmol) and N,N-diisopropylethylamine (0.063 mL, 0.36mmol) in N,N-dimethylformamide (DMF) (0.6 mL) was heated to 70° C. for18 h. The cooled reaction mixture was evaporated, redissolved inacetonitrile (0.5 mL) and ethanol (0.15 mL) and sodium hydroxide (10 M,0.1 mL) was added. The solution was stirred at 40° C. for 18 h. Thecooled reaction mixture was evaporated, redissolved in DMSO:MeOH (1:1, 1mL) and water (0.1 mL). The residue purified by MDAP using a high pHammonium carbonate buffer (pH 10) to give the title compound ammonium3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-(5-isopropyl-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)methyl)-4-methylphenyl)propanoate(17.0 mg, 33.9% yield). LC-MS m/z 502.24 (M+H)+, 0.67 min (ret. time).

The compounds in Table 5 were prepared by a method similar to the onedescribed for the preparation of ammonium3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-(5-isopropyl-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)methyl)-4-methylphenyl)propanoate.As is appreciated by those skilled in the art, these analogous examplesmay involve variations in general reaction conditions.

TABLE 5 LCMS Retention Ex # Structure Name [M + H]⁺ Time (min) Example11

Ammonium 3-(1,4- dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-3-(3-((2-isopropyl-5,6- dihydropyrido[3,4- d]pyrimidin-7(8H)- yl)methyl)-4-methylphenyl) propanoate 499.21 0.73 Example 12

Ammonium 3-(1,4- dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-3-(3-((2-(5-ethyl-1,2,4-oxadiazol- 3-yl)piperidin-1- yl)methyl)-4- methylphenyl)propanoate 503.26 0.78 Example 13

Ammonium 3-(1,4- dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl- 5,6-dihydropyrido [3,4-d]pyrimidin-7(8H)-yl)methyl)-4- methylphenyl) propanoate 485.23 0.65 Example 14

Ammonium 3-(3-((7- cyano-2,3- dihydrobenzo[f][1,4] oxazepin-4(5H)-yl)methyl)-4- methylphenyl)-3- (1,4-dimethyl-1H- benzo[d][1,2,3]triazol-5-yl) propanoate 496.24 0.71 Example 15

Ammonium 3-(3-(((2- bromobenzyl)(methyl) amino)methyl)-4- methylphenyl)-3-(1,4-dimethyl-1H- benzo[d][1,2,3] triazol-5-yl) propanoate 521.15 0.65Example 16

Ammonium 3-(3-(((4- bromobenzyl)(methyl) amino)methyl)-4- methylphenyl)-3-(1,4-dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)propanoate 521.15 0.68Example 17

Ammonium 3-(3-(((3- bromobenzyl)(methyl) amino)methyl)-4- methylphenyl)-3-(1,4-dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)propanoate 521.19 0.68

Example 183-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-methyl-2-(p-tolyl)morpholino)methyl)phenyl)propanoicacid, formic acid salt

A mixture of ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(0.0347 g, 0.09 mmol), 2-methyl-2-(p-tolyl)morpholine (0.0258 g, 0.135mmol) and N,N-diisopropylethylamine (0.063 mL, 0.36 mmol) inN,N-dimethylformamide (DMF) (0.6 mL) was heated to 70° C. for 18 h. Thecooled reaction mixture was evaporated, redissolved in acetonitrile (0.5mL) and ethanol (0.15 mL). Sodium hydroxide (10 M, 0.1 m L) was added.The solution was stirred at 40° C. for 18 h. The cooled reaction mixturewas evaporated, redissolved in DMSO:MeOH (1:1, 1 mL) and water (0.1 mL).The residue was purified by MDAP using a high pH ammonium carbonatebuffer (pH 10). Impure compound was redissolved in DMSO (1 mL) and theresidue was purified by MDAP using a formic acid modifier to give thetitle compound3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-methyl-2-(p-tolyl)morpholino)methyl)phenyl)propanoicacid, formic acid salt (20.8 mg, 40.6% yield). LC-MS m/z 513.25 (M+H)⁺,0.82 min (ret. time).

The compounds in Table 6 were prepared by a method similar to the onedescribed for the preparation of3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-(5-isopropyl-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)methyl)-4-methylphenyl)propanoicacid, formic acid salt. As is appreciated by those skilled in the art,these analogous examples may involve variations in general reactionconditions.

TABLE 6 LCMS Retention Ex # Structure Name [M + H]⁺ Time (min) Example19

3-(1,4-dimethyl-1H- benzo[d][1,2,3]triazol-5- yl)-3-(3-((1-ethyl-3,4-dihydropyrrolo[1,2- a]pyrazin-2(1H)-yl) methyl)-4-methylphenyl)propanoic acid, formic acid salt 472.26 0.70 Example 20

3-(3-((cyclopropyl(4- methoxybenzyl)amino) methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H- benzo[d][1,2,3]triazol-5- yl)propanoic acid, formicacid salt 499.22 0.73 Example 21

3-(1,4-dimethyl-1H- benzo[d][1,2,3]triazol-5- yl)-methoxyphenyl)morpholino)methyl)-4- methylphenyl)propanoic acid, formic acid salt515.20 0.78

Example 223-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, trifluoroacetic acid

1-(((4-Chloropyridin-3-yl)methyl)amino)-2-methylpropan-2-ol

To a solution of 4-chloronicotinaldehyde (0.425 g, 3 mmol) in methanol(10 mL) was added 1-amino-2-methylpropan-2-ol (0.281 g, 3.15 mmol). Thereaction mixture was stirred at ambient temperature for 3 h afterwhichtime NaBH₄ (0.057 g, 1.500 mmol) was added. The resulting reactionmixture was stirred at ambient temperature for 1 h. The reaction mixturewas concentrated and redissolved in DCM (15 mL), dried over MgSO₄,filtered, then evaporated under vacuum to afford product1-(((4-chloropyridin-3-yl)methyl)amino)-2-methylpropan-2-ol (0.657 g,3.06 mmol, 102% yield). LC-MS m/z 215.1 (M+H)⁺, 0.19 min (ret. time).

2,2-Dimethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine

To a solution of1-(((4-chloropyridin-3-yl)methyl)amino)-2-methylpropan-2-ol (0.656 g,3.06 mmol) in dimethyl sulfoxide (8 mL) was added KOtBu (0.686 g, 6.11mmol). The resulting reaction mixture was stirred at 80° C. for 20 h. Tothe reaction mixture was added sodium bicarbonate (0.513 g, 6.11 mmol)and stirred at 80° C. for 2 h. The reaction mixture was filtered thenevaporated down afterwhich time it was redissolved in DCM (20 mL), driedover K₂CO₃, filtered, concentrated to afford desired product2,2-dimethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine (0.432 g,2.424 mmol, 79% yield). LC-MS m/z 178.9 (M+H)⁺, 0.25 min (ret. time).

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, trifluoroacetic acid

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(76 mg, 0.2 mmol) in dichloromethane (1 mL) was added SOCl₂ (0.029 mL,0.400 mmol). The resulting reaction mixture was stirred at ambienttemperature for 10 min and then concentrated. To this crude was addedthe solution of2,2-dimethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine (178 mg,1.000 mmol) and DIEA (0.140 mL, 0.800 mmol) in tetrahydrofuran (1 mL)and acetonitrile (2 mL). The resulting reaction mixture was heated withmicrowave at 100° C. for 1 h. The reaction mixture was evaporated undervacuum, redissolved in methanol (3 mL) then NaOH (3.0 N) (0.533 mL,1.600 mmol) was added. The resulting reaction mixture was heated withmicrowave at 130° C. for 60 min. The reaction mixture was then acidifiedwith HCl (2 N) to pH 6, evaporated under vacuum, purified by reversephase HPLC to afford desired product3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, trifluoroacetic acid (18.0 mg, 0.034 mmol, 17.06% yield). LC-MSm/z 528.2 (M+H)⁺, 0.88 min (ret. time).

Example 233-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, trifluoroacetic acid

1-(((2-Chloropyridin-3-yl)methyl)amino)-2-methylpropan-2-ol

To a solution of 2-chloronicotinaldehyde (1.44 g, 10.17 mmol) inmethanol (30 mL) was added 1-amino-2-methylpropan-2-ol (0.952 g, 10.68mmol). The reaction mixture was stirred at ambient temperature for 30min, then NaBH₄ (0.192 g, 5.09 mmol) was added. The resulting reactionmixture was stirred at ambient temperature for 1 h. More NaBH₄ (0.077 g,2.035 mmol) was added. The resulting reaction mixture was stirred atambient temperature for 17 h and then concentrated. It was redissolvedin DCM (50 mL), dried over MgSO₄, filtered then evaporated under vacuumto afford product1-(((2-chloropyridin-3-yl)methyl)amino)-2-methylpropan-2-ol (2.6017 g,12.12 mmol, 119% yield). LC-MS m/z 215.2 (M+H)⁺, 0.33 min (ret. time).

2,2-Dimethyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine

To a solution of1-(((2-chloropyridin-3-yl)methyl)amino)-2-methylpropan-2-ol (0.859 g,4.0 mmol) in dimethyl sulfoxide (10 mL) was added KOtBu (0.898 g, 8.00mmol). The resulting reaction mixture was stirred at 80° C. for 65 h. Tothe reaction mixture was added sodium bicarbonate (0.672 g, 8.00 mmol)then stirred at 80° C. for 1 h. The reaction mixture was filtered,evaporated down, redissolved in DCM (20 mL), dried over K₂CO₃, filtered,evaporated under vacuum to afford desired product2,2-dimethyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.6151 g,3.45 mmol, 86% yield). LC-MS m/z 178.9 (M+H)⁺, 0.20 min (ret. time).

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, trifluoroacetic acid

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(76 mg, 0.2 mmol) in dichloromethane (1 mL) was added SOCl₂ (0.029 mL,0.400 mmol). The resulting reaction mixture was stirred at ambienttemperature for 10 min and then concentrated. A solution of2,2-dimethyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (71.3 mg,0.400 mmol), DIEA (0.140 mL, 0.800 mmol) in tetrahydrofuran (1 mL) andacetonitrile (2 mL) was added. The resulting reaction mixture was heatedwith microwave at 100° C. for 1 h. To the reaction mixture was addedmore DIEA (0.070 mL, 0.400 mmol) then heated with microwave at 100° C.for 1 h. The reaction mixture was evaporated under vacuum thenredissolved in methanol (3 mL) and NaOH (3.0 N) (0.533 mL, 1.600 mmol)was added. The resulting reaction mixture was heated with microwave at140° C. for 1 h. The reaction mixture was acidified with HCl (2 N) to pH6, evaporated under vacuum, purified by reverse phase HPLC to afforddesired product3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, trifluoroacetic acid (65.1 mg, 0.123 mmol, 61.7% yield). LC-MS m/z528.3 (M+H)⁺, 0.73 min (ret. time).

Example 24(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, formic acid salt

(R)-1-Aminobutan-2-ol

To a solution of NH₄OH (˜28% solution in H₂O) (36.3 mL, 261 mmol) wasadded (R)-2-ethyloxirane (2.246 mL, 26.1 mmol). The resulting reactionmixture was stirred at ambient temperature for 18 h. The reactionmixture was concentrated under reduced pressure to afford the desiredproduct (R)-1-aminobutan-2-ol (2.488 g, 19.54 mmol, 74.9% yield). ¹H NMR(400 MHz, CHLOROFORM-d) b ppm 0.97 (t, J=7.53 Hz, 3H) 1.42-1.53 (m, 2H)1.71 (br. s., 3H) 2.47-2.59 (m, 1H) 2.85 (dd, J=12.80, 3.26 Hz, 1H)3.39-3.49 (m, 1H).

4-Bromonicotinaldehyde

To a solution of 4-bromopyridine hydrochloride (50 g, 257 mmol) intetrahydrofuran (THF) (250 mL) was added LDA 2M solution in THF (250 mL,500 mmol) at −78° C. and stirred for 1 h. DMF (19.91 mL, 257 mmol) wasadded at −78° C. It was stirred for 1 h at this same temperature. Thereaction mixture was warmed to ambient temperature and stirred for 16 h.The reaction mixture was cooled to 0° C., quenched with 2 N HCl andextracted twice with EtOAc. The organic layer was dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated to give the titlecompound (13 g, 69.9 mmol, 27.2% yield) as brown colored liquid. GCMS:rt=6.59 mins, M⁺=185.0

(R)-1-(((4-Bromopyridin-3-yl)methyl)amino)butan-2-ol

To a solution of (R)-1-aminobutan-2-ol (1.677 g, 18.82 mmol) in methanol(30 mL) and was added 4-bromonicotinaldehyde (3.5 g, 18.82 mmol) atambient temperature. Then NaOH (18.82 mL, 18.82 mmol) was added at 0° C.The reaction mixture was stirred at ambient temperature for 1 hafterwhich time NaBH₄ (0.712 g, 18.82 mmol) was added portionwise at 0°C. The reaction mixture was stirred for 48 h at ambient temperature. Thereaction mixture was concentrated and then quenched with cold water,extracted with EtOAc and washed with brine solution. The organic layerwas dried over Na₂SO₄, filtered and then concentrated. The crude productwas purified with silica gel chromatography to give the title compound(5 g, 15.58 mmol, 83% yield) as liquid. LC-MS m/z 261.12 (M+H)⁺, 2.49min (ret. time).

(R)-2-Ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine

To a solution of (R)-1-(((4-bromopyridin-3-yl)methyl)amino)butan-2-ol(800 mg, 3.09 mmol) in isopropanol (30 mL) was added Cs₂CO₃ (2012 mg,6.17 mmol) at ambient temperature, followed by copper(I) iodide (588 mg,3.09 mmol). The reaction mixture was heated in a microwave reactor for 1h at 95° C. The reaction mixture was filtered though celite and washedwith ethyl acetate. The filtrate was concentrated and was purified withsilica gel chromatography to give the title compound (590 mg, 2.70 mmol,87% yield) as liquid. LC-MS m/z 179.26 (M+H)⁺, 2.58 min (ret. time).

(R)-tert-Butyl2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepine-4(5H)-carboxylate

To a solution of(R)-2-ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine (2.5 g, 14.03mmol) in THF (20 mL) was added TEA (0.313 mL, 2.244 mmol) at ambienttemperature. Di-tert-butyl dicarbonate (6.51 mL, 28.1 mmol) was added at0° C. The reaction mixture was stirred at ambient temperature for 2 h.The reaction mixture was quenched with water and extracted with ethylacetate, washed with brine solution, dried over Na₂SO₄, filtered andconcentrated. It was purified with silica gel chromatography to give thetitle compound (3.5 g, 11.53 mmol, 82% yield) as liquid. LC-MS m/z279.24 (M+H)⁺, 1.60 min (ret. time).

(R)-2-Ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine hydrochlorideHCl

To a solution of (R)-tert-butyl2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepine-4(5H)-carboxylate (3.5 g,12.57 mmol) in 1,4-dioxane (20 mL) was added 4 M HCl in dioxane (3 mL,12.00 mmol) at 0° C. The reaction mixture was stirred at ambienttemperature for 1 h. The reaction mixture was concentrated to obtain asolid. The solid was washed with diethyl ether and hexane to give thetitle compound (2.1 g, 9.43 mmol, 75% yield). LC-MS m/z 179.0 (M+H)⁺,2.78 min (ret. time).

(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methanol

tert-Butyllithium (19.52 mL, 33.2 mmol) was added dropwise to a solutionof 5-bromo-1,4-dimethyl-1H-benzo[d][1,2,3]triazole (3.91 g, 17.31 mmol)in tetrahydrofuran (THF) (108 ml) at −78° C. under a nitrogen atmosphereand stirred for 30 minutes. A solution of3-(((4-methoxybenzyl)oxy)methyl)-4-methylbenzaldehyde (3.9 g, 14.43mmol) in tetrahydrofuran (THF) (36.1 ml) was then added dropwise andstirred at −78° C. for 1.5 hours followed by warming to room temperatureand stirring for an additional hour. Saturated aqueous ammonium chloride(100 mL) was added to the solution. Same scale reaction was runned sideby side. The 2 batches were combined and the mixture was extracted withethyl acetate (3×100 mL). The combined organic fractions were washed(brine), dried (sodium sulfate), filtered and the solvent wasconcentrated. The crude product was purified by silica gelchromotagraphy to give title compound (8.8 g, 21.08 mmol, 73.0% yield).LC/MS: m/z 418.0 (M+H)⁺, 1.11 min (ret. time). 1H NMR (400 MHz,CHLOROFORM-d) δ=7.76-7.69 (m, 1H), 7.34 (s, 2H), 7.24 (d, J=8.3 Hz, 2H),7.21-7.12 (m, 2H), 6.87 (d, J=8.3 Hz, 2H), 6.27 (s, 1H), 4.49 (d, J=5.0Hz, 4H), 4.29 (s, 3H), 3.83 (s, 3H), 2.81 (s, 3H), 2.31 (s, 3H), 2.07(s, 1H)

Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate

2,2,2-trichloroacetonitrile (4.23 ml, 42.2 mmol) and DBU (0.146 ml,1.054 mmol) were added sequentially to a solution of(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methanol(8.8 g, 21.08 mmol) in acetonitrile (263 ml) at ambient temperature andstirred for 45 minutes.((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (9.19 g, 52.7mmol) followed by1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (0.593g, 2.108 mmol) were then added and the solution stirred at ambienttemperature for 2 h. The reaction was quenched with saturated sodiumbicarbonate (10 mL) and extracted with DCM (3×15 mL), dried over sodiumsulfate, filtered and concentrated. The residue was redissolved indichloromethane (DCM) (263 mL). Water (15.19 mL, 843 mmol) was added andthe solution was cooled to 0° C.,4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (9.57 g,42.2 mmol) was added. The solution was stirred at 0° C. for 1 h. Thereaction was quenched with saturated sodium bicarbonate (10 mL) andextracted with DCM (3×15 mL) and dried over sodium sulfate. The crudeproduct was purified by flash chromatography on a silica gelchromatography to give the title compound (6.9 g, 18.09 mmol, 86%yield). LC/MS: m/z 382.0 (M+H)⁺, 1.00 min (ret. time).

Methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(2200 mg, 5.77 mmol) in dichloromethane (DCM) (10 mL) at 25° C. wasadded thionyl chloride (0.842 mL, 11.53 mmol). The mixture was stirredat 25° C. for 40 min. The reaction mixture was concentrated to give thetitle compound (2200 mg, 5.50 mmol, 95% yield). LC-MS m/z 399.9 (M)⁺,1.14 min (ret. time).

Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

To a solution of methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(1380 mg, 3.45 mmol) in acetonitrile (8 mL) at 25° C. was added(R)-2-ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine, hydrochloride(889 mg, 4.14 mmol) and DIEA (2.411 mL, 13.80 mmol). The reactionmixture was heated in a Biotage microwave at high absorption for 1 h at120° C. The solvent was removed under reduced pressure and the residuethen purified by silica gel chromatography. The desired fractions wereconcentrated under reduced pressure to give the title compound (1000 mg,1.846 mmol, 53.5% yield). LC-MS m/z 542.4 (M+H)⁺, 0.82 min (ret. time).

(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate(1000 mg, 1.846 mmol) in methanol (8 mL) at 25° C. was added LiOH (5.54mL, 11.08 mmol). The reaction mixture was heated in a Biotage microwaveat high absorption for 2 h at 120° C. This reaction was repeated with1.5 g of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoateand 8.3 mL LiOH in 10 mL MeOH. Both batches were combined and thenacidified with 6H HCl to pH 1 and extracted with ethyl acetate twice.The aqueous layer was basified with 2M LiOH to pH 5. It was extractedwith ethyl acetate twice. The combined organic layer was washed withwater twice and then brine and concentrated to give the crude product(1350 mg). The water layer was extracted with 4:1 DCM and IPA to obtainanother impure batch (900 mg crude). The impure batch was purified withpreparative HPLC under acidic conditions. Fractions were concentratedand combined with the 1.35 g batch. The combined batch was purified withchiral SFC (Column: Chiralpak AD 20×250 mm; Co-solvent:20% EtOH;Flowrate: 50 g/min; Back presure: 100 Bar).(S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid (654 mg, 1.239 mmol) was obtained as solid. LC-MS m/z 528.3 (M+H)⁺,0.83 min (ret. time). (chiral SFC ret. time: 7.52 min)

(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, formic acid salt

To a suspension of (S)-methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(100 mg, 0.262 mmol) in dichloromethane (DCM) (2 mL) was added thionylchloride (0.038 mL, 0.524 mmol). The mixture was stirred at ambienttemperature for 30 min and the solvent removed. The residue wasre-dissolved in acetonitrile (2 mL), DIEA (0.183 mL, 1.049 mmol) and(R)-2-ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine hydrochloride(56.3 mg, 0.262 mmol) were added. The resulting reaction mixture washeated in a Biotage microwave at high absorption for 1 h at 120° C., thesolvent was removed and the residue was purified by silica gelchromatography to give the intermediate. It was re-dissolved in MeOH (2mL) and 2M LiOH (0.786 mL, 1.573 mmol) was added and the reactionmixture was heated in a Biotage microwave at high absorption for 2 h at120° C. It was acidified with 6N HCl and 0.5 mL DMSO was added. It wasconcentrated to give the crude material. The crude product was purifiedby reverse-phase HPLC (with 0.1% formic acid condition) to give thetitle compound (61 mg, 0.106 mmol, 40.6% yield). LC-MS m/z 528.3 (M+H)⁺,0.77 min (ret. time).

The compounds in Table 7 were prepared by a method similar to the onedescribed for the preparation of(S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid. As is appreciated by those skilled in the art, these analogousexamples may involve variations in general reaction conditions.

TABLE 7 LCMS Retention Ex # Structure Name [M + H]⁺ Time (min) Example25

(S)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9- fluoro-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) methyl)-4- methylphenyl)-2,2- dimethylpropanoic acid,trifluoroacetic acid salt 527.4 0.81 Example 26

(S)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl- 2,3-dihydrobenzo[f] [1,4]oxazepin-4(5H)-yl)methyl)-4- methylphenyl)-2,2- dimethylpropanoic acid, trifluoroaceticacid salt 527.4 0.81 Example 27

(R)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl- 2,3-dihydrobenzo[f] [1,4]oxazepin-4(5H)-yl)methyl)-4- methylphenyl)-2,2- dimethylpropanoic acid 527.6 0.81 Example28

(S)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9- fluoro-2,3- dihydropyrido[3,4-f][1,4]oxazepin-4(5H)- yl)methyl)-4- methylphenyl)-2,2-dimethylpropanoic acid 546.5 0.90 Example 29

(S)-3-(3-(((R)-8- Chloro-2-ethyl-2,3- dihydropyrido[3,4-f][1,4[oxazepin- 4(5H)-yl)methyl)- 4-methylphenyl)-3- (1,4-dimethyl-1H-benzo[d][1,2,3] triazol-5-yl)-2,2- dimethylpropanoic acid 562.5 0.93Example 30

(S)-Methyl 3-(1,4- dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl- 2,3-dihydropyrido[2,3- f][1,4]oxazepin-4(5H)-yl)methyl)-4- methylphenyl)-2,2- dimethylpropanoate, formic acid salt528.5 0.93

Example 313-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-6-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, formic acid salt

Methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(500 mg, 1.311 mmol) in dichloromethane (DCM) (5 mL) was added thionylchloride (0.191 mL, 2.62 mmol). The mixture was stirred at ambienttemperature for 40 min. The reaction mixture was concentrated to givethe title compound (515 mg, 1.288 mmol, 98% yield) as solid. LC-MS m/z400.1 (M+H)⁺, 1.13 min (ret. time).

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-6-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, formic acid salt

To a suspension of methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(50 mg, 0.125 mmol) in acetonitrile (2 mL) was added(R)-2-ethyl-6-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepinehydrochloride (29.0 mg, 0.125 mmol) and DIEA (0.066 mL, 0.375 mmol). Theresulting reaction mixture was heated with microwave at 120° C. for 1 h.The reaction mixture was concentrated and the resulting residue wasre-dissolved in MeOH (2 mL) and 2M LiOH (0.063 mL, 0.125 mmol) was addedand the reaction mixture was heated in a Biotage microwave at highabsorption for 3 h at 120° C. It was acidified with 6N HCl and 0.5 mLDMSO was added. It was concentrated and purified by reverse-phase HPLC(with 0.1% formic acid condition) to give the title compound (25.6 mg,0.046 mmol, 36.7% yield). LC-MS m/z 545.3 (M+H)⁺, 0.85 min (ret. time).

The compounds in Table 8 were prepared by a method similar to the onedescribed for the preparation of3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-6-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, formic acid salt. As is appreciated by those skilled in the art,these analogous examples may involve variations in general reactionconditions.

TABLE 8 LCMS Retention Ex # Structure Name [M + H]⁺ Time (min) Example32

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5- yl)-3-(3-(((R)-2-ethyl-7-fluoro-2,3- dihydrobenzo[f][1,4] oxazepin-4(5H)-yl) methyl)-4-methylphenyl)-2,2- dimethylpropanoic acid, formic acid salt 545.4 0.84Example 33

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5- yl)-3-(3-(((R)-2-ethyl-8-fluoro-2,3- dihydrobenzo[f][1,4] oxazepin-4(5H)-yl) methyl)-4-methylphenyl)-2,2- dimethylpropanoic acid, formic acid salt 545.3 0.86Example 34

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5- yl)-3-(3-(((R)-2-ethyl-9-fluoro-2,3- dihydrobenzo[f][1,4] oxazepin-4(5H)-yl) methyl)-4-methylphenyl)-2,2- dimethylpropanoic acid, formic acid salt 545.3 0.84Example 35

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-3-(3-((9-fluoro-2,2-dimethyl-2,3- dihydrobenzo[f][1,4] oxazepin-4(5H)-yl) methyl)-4-methylphenyl)-2,2- dimethylpropanoic acid 545.4 0.94 Example 36

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-3-(3-((4-ethyl-6-fluoro-4,5-dihydro-1H- benzo[c]azepin-2(3H)- yl)methyl)-4-methylphenyl)-2,2- dimethylpropanoic acid 543.5 0.94 Example 37

3-(3-((6,7-Dihydro- 5H-imidazo[1,5- a][1,4]diazepin-8(9H)- yl)methyl)-4-methylphenyl)-3- (1,4-dimethyl-1H- benzo[d][1,2,3] triazol-5-yl)-2,2-dimethylpropanoate, Sodium salt 487.3 0.64

Example 38(2R,3S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid, formic acid salt

1,4-Dimethyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde

A solution of BuLi (1.6 M in Hexanes) (9.12 mL, 14.60 mmol) andethylmagnesium bromide (1.0 M in THF) (6.64 mL, 6.64 mmol) in toluene(40 mL) was prepared at −40° C. The resulting solution was stirred at−40° C. for 40 minutes after which time a solution of5-bromo-1,4-dimethyl-1H-benzo[d][1,2,3]triazole (3000 mg, 13.27 mmol) intetrahydrofuran (THF) (15 mL) was added. The resulting dark coloredsolution was allowed to stir for 1 h during which time the cooling bathwarmed to −15° C. To the resulting solution was added DMF (6.16 mL, 80mmol). During the addition a heavy, viscous precipitate formed. Theresulting suspension was stirred at −15° C.-−10° C. for 1 h then removedfrom the cooling bath. After a further 2 h, the reaction was quenchedwith saturated ammonium chloride solution and diluted with water andethyl acetate. The bilayer was separated and the aqueous phase extractedwith ethyl acetate (1×). The combined organics were washed with brine(1×), and concentrated. It was purified by silica gel chromatography togive the title compound (1.59 g, 9.08 mmol, 68.4% yield) as yellowsolid. LC-MS m/z 176.2 (M+H)⁺, 0.56 min (ret. time).

(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methanol

To a solution of4-bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene (2244 mg, 6.99mmol) in tetrahydrofuran (THF) (30 mL) at −78° C. was addedn-butyllithium (4.37 mL, 6.99 mmol) slowly. The reaction mixture wasstirred for 30 min at −78° C. and then a solution of1,4-dimethyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde (1020 mg, 5.82mmol) in THF (5 mL) was added slowly. The reaction mixture was stirredat −78° C. for 1 h. The reaction was quenched with saturated ammoniumchloride. The organic layer was concentrated to give the crude product.It was purified by silica gel chromatography to give the title compound(1.5 g, 3.59 mmol, 61.7% yield). LC-MS m/z 418.1 (M+H)⁺, 1.05 min (ret.time).

Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2-methylpropanoate

To a solution of(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methanol(1.5 g, 3.59 mmol) in acetonitrile (20 mL) was added DBU (0.016 mL,0.108 mmol) slowly followed by addition of 2,2,2-trichloroacetonitrile(0.540 mL, 5.39 mmol). The reaction mixture was stirred for 30 min atambient temperature. Then(E)-((1-methoxyprop-1-en-1-yl)oxy)trimethylsilane (1.655 mL, 8.98 mmol)was added followed by1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (0.071g, 0.251 mmol). The mixture was stirred at ambient temperature for 3 h.1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (0.071g, 0.251 mmol) and (E)-((1-methoxyprop-1-en-1-yl)oxy)trimethylsilane(1.655 mL, 8.98 mmol) were added and stirred for another 19 h. It wasquenched with saturated NH₄Cl, extracted with ethyl acetate twice. Thecombined organic layer was concentrated to give the crude residue. Itwas purified by silica gel chromatography to give the title compound(766 mg, 1.571 mmol, 43.7% yield) LC-MS m/z 488.4 (M+H)+, 1.19, 1.22 min(ret. time).

(2R,3S)-Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2-methylpropanoateand (2S,3R)-methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2-methylpropanoate

Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2-methylpropanoate(766 mg, 1.571 mmol, 43.7% yield) was separated by preparative HPLCunder acidic conditions to give isomer 1 (300 mg) and isomer 2 (280 mg).

Isomer 2 (280 mg, 0.574 mmol) from above was separated by chiral SFC(Column: Chiral pack AD 20×250 mm 5 u; Co-solvent: 25% EtOH; Flow rate:50 g/min; Back pressure: 100 Bar) to give (2R,3S)-methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2-methylpropanoate(93 mg, 0.191 mmol, 33.2% yield) (chiral SFC ret. time: 3.71 min) and(2S,3R)-methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2-methylpropanoate(93 mg, 0.191 mmol, 33.2% yield). (chiral SFC ret. time: 6.42)

(2R,3S)-Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate

DDQ (47.6 mg, 0.210 mmol) was added to a vigorously stirring, biphasicsolution of (2R,3S)-methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2-methylpropanoate(93 mg, 0.191 mmol) in dichloromethane (DCM) (2 mL) and water (0.200 mL)at ambient temperature. The reaction flask was covered with aluminumfoil. Over the course of 2 h, the reaction mixture turned from deepgreen color to light grey. It was quenched with water and extracted withDCM twice (2×5 mL). The organic layer was dried over sodium sulfate,filtered and concentrated to give the title compound (71 mg, 0.193 mmol,101% yield). LC-MS m/z 368.2 (M+H)⁺, 0.89 min (ret. time).

(2R,3S)-Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoate

To a suspension of (2R,3S)-methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(70 mg, 0.191 mmol) in dichloromethane (DCM) (2 mL) was added thionylchloride (0.028 mL, 0.381 mmol). The mixture was stirred for 30 min. Thesolvent was removed under reduced pressure and the resulting residue wasre-dissolved in dichloromethane (DCM) (2 mL). DIEA (0.133 mL, 0.762mmol) and (R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepinehydrochloride (48.9 mg, 0.229 mmol) were added. The resulting reactionmixture was heated with microwave at 120° C. for 1 h. It wasconcentrated to give the title compound (65 mg, 0.123 mmol, 64.8%yield). LC-MS m/z 527.6 (M+H)⁺, 0.87 min (ret. time).

(2R,3S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid, formic acid salt

To a solution of (3S)-methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoate(30 mg, 0.057 mmol) in methanol (2 mL) was added 2 M LiOH (0.171 mL,0.342 mmol). The mixture was stirred at ambient temperature for 3 days.More 2 M LiOH (0.171 mL, 0.342 mmol) was added and stirred at ambienttemperature for 8 days. It was acidified with 6 N HCl and 0.5 mL DMSOwas added. It was concentrated and purified by reverse-phase HPLC (with0.1% formic acid condition) to give the title compound (15 mg, 0.029mmol, 51.4% yield). LC-MS m/z 513.6 (M+H)⁺, 0.81 min (ret. time).

Example 39(2S,3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid

(2R,3S)-Benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoateand (2S,3R)-benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate

DDQ (443 mg, 1.951 mmol) was added to a vigorously stirring, biphasicsolution of racemic benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2-methylpropanoate(1000 mg, 1.774 mmol) in dichloromethane (DCM) (20 mL) and water (2.000mL) at ambient temperature. The reaction flask was covered with aluminumfoil. Over the course of 2 h, the reaction mixture turned from deepgreen color to light grey. It was quenched with water and extracted withDCM twice (2×10 mL). The organic layer was washed with water (3×4 mL)and concentrated to give the title compound. It was purified byreverse-phase HPLC (with 0.1% TFA condition) to separate twodiastereomers to obtain Peak 1 (337.5 mg) and peak 2 (385.2 mg). Sincethe reverse phase HPLC with acidic modifier, by-product benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methyl-3-(4-methyl-3-((2,2,2-trifluoroacetoxy)methyl)phenyl)propanoatewas also observed with both batches of peak 1 and peak 2.

To a solution of peak 1 (benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoateand benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methyl-3-(4-methyl-3-((2,2,2-trifluoroacetoxy)methyl)phenyl)propanoate(337 mg, 0.760 mmol) in dichloromethane (DCM) (8 mL) was added Et₃N(0.106 mL, 0.760 mmol). The mixture was stirred at ambient temperaturefor 1 h. Solvent was removed under reduced pressure and the residue thesample was separated by Chiral SFC (Column: Chiralpak IC 20×150 mm;Co-solvent: 25% IPA; Flowrate: 50 g/min; Back pressure: 100 Bar) to givesingle enantiomerically pure (2R,3S)-benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(144 mg, 0.325 mmol, 42.7% yield) (chiral SFC ret. time: 8.93 min) andsingle enantiomerically pure (2S,3R)-benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(99.3 mg, 0.224 mmol, 29.5% yield) (chiral SFC ret. time: 11.2 min).

(2R,3R)-Benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoateand (2S,3S)-benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate

To a solution of peak 2 (benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoateand benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methyl-3-(4-methyl-3-((2,2,2-trifluoroacetoxy)methyl)phenyl)propanoate(410 mg, 0.920 mmol) in dichloromethane (DCM) (8 mL) was added Et₃N(0.128 mL, 0.920 mmol). The mixture was stirred at ambient temperaturefor 1 h. Sovlent was concentrated. It was separated by Chiral SFC(Column: Chiralpak IC 20×150 mm; Co-solvent: 20% MeOH; Flowrate: 50mg/min; Back pressure: 100 Bar) to give single enantiomerically purediastereomer (2R,3R)-benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(117 mg, 0.264 mmol, 34.7% yield) (chiral SFC ret. time: 10.08 min) andsingle enantiomerically pure diastereomer (2S,3S)-benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(199 mg, 0.449 mmol, 59.1% yield) (chiral SFC ret. time: 11.32 min).

(2S,3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid

To a solution of (2S,3R)-benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(30 mg, 0.068 mmol) in dichloromethane (DCM) (1 mL) was added thionylchloride (9.87 μL, 0.135 mmol). The mixture was stirred at ambienttemperature for 40 min. The solvent was concentrated and the resultingresidue was re-dissolved in acetonitrile (1.000 mL),(R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride(21.68 mg, 0.101 mmol) and DIEA (0.047 mL, 0.271 mmol) was added. Thereaction mixture was heated in a Biotage microwave at high absorptionfor 1 h at 120° C. The solvent was concentrated and the resultingresidue was re-dissolved in EtOAc (2 mL). It was passed though H-Cube (1mL/min, Pd/C cartridge, 25° C.) for 3 h. The solvent was removed underreduced pressure and the residue was purified by reverse-phase HPLC togive the title compound (23.4 mg, 0.046 mmol, 67.5% yield). LC-MS m/z513.6 (M+H)⁺, 0.83 min (ret. time).

Example 40(2R,3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid

To a solution of (2R,3R)-benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(30 mg, 0.068 mmol) in dichloromethane (DCM) (1 mL) was added thionylchloride (9.87 μl, 0.135 mmol). The mixture was stirred at ambienttemperature for 40 min. The solvent was concentrated and the resultingresidue was re-dissolved in acetonitrile (1 mL),(R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride(21.68 mg, 0.101 mmol) and DIEA (0.047 mL, 0.271 mmol) was added. Thereaction mixture was heated in a Biotage microwave at high absorptionfor 1 h at 120° C. The solvent was concentrated and the resultingresidue was re-dissolved in EtOAc (2 mL). It was passed though H-Cube (1mL/min, cartridge Pd/C, 25° C.) for 3 h. The solvent was removed underreduced pressure and the residue was purified by reverse-phase HPLC togive the title compound (22.5 mg, 0.044 mmol, 64.9% yield). LC-MS m/z513.5 (M+H)⁺, 0.83 min (ret. time).

Example 41(2S,3S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid

To a solution of (2S,3S)-benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(30 mg, 0.068 mmol) in dichloromethane (DCM) (1 mL) was added thionylchloride (9.87 μL, 0.135 mmol). The mixture was stirred at ambienttemperature for 40 min. The solvent was concentrated and the resultingresidue was re-dissolved in acetonitrile (1.000 mL),(R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride(21.68 mg, 0.101 mmol) and DIEA (0.047 mL, 0.271 mmol) was added. Thereaction mixture was heated in a Biotage microwave at high absorptionfor 1 h at 120° C. The solvent was concentrated and the resultingresidue was re-dissolved in EtOAc (2 mL). It was passed though H-Cube (1mL/min, cartridge Pd/C, 25° C.) for 3 h. The solvent was removed underreduced pressure and the residue was purified by reverse-phase HPLC togive the title compound (18 mg, 0.035 mmol, 51.9% yield). LC-MS m/z513.5 (M+H)⁺, 0.83 min (ret. time).

Example 42(3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-7-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid, trifluoroacetic acid salt

(3R)-Benzyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate

To a solution of (3R)-Benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(150 mg, 0.338 mmol) in dichloromethane (DCM) (2 mL) was added thionylchloride (0.049 mL, 0.676 mmol). The mixture was stirred at ambienttemperature for 40 min. The reaction mixture was concentrated to givethe title compound (153 mg, 0.331 mmol, 98% yield) as a white solid.LC-MS m/z 462.2 (M+H)⁺, 1.23 min (ret. time).

(3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-7-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid, trifluoroacetic acid salt

To a mixture of (3R)-benzyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate(32 mg, 0.069 mmol) in acetonitrile (4 mL) was added(R)-2-ethyl-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (20.28 mg,0.104 mmol) and DIEA (0.048 mL, 0.277 mmol). The resulting reactionmixture was heated with microwave at 120° C. for 1 h. The reactionmixture was concentrated to give (3R)-benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-7-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoate.The crude material was re-dissolved in ethyl acetate (4 mL). Thesolution was passed though H-Cube (flow rate: 1 mL/min, 25° C.,cartridge: 10% Pd/C) for 1.5 h. It was concentrated and purified byreverse-phase HPLC to give the title compound (30.9 mg, 0.058 mmol, 84%yield) was obtained. LC-MS m/z 531.4 (M+H)⁺, 0.87 min (ret. time). 1HNMR (400 MHz, METHANOL-d4) δ=7.81 (d, J=8.8 Hz, 1H), 7.62-7.47 (m, 3H),7.37 (d, J=7.8 Hz, 1H), 7.17 (d, J=3.8 Hz, 2H), 6.89 (d, J=8.0 Hz, 1H),4.68-4.45 (m, 3H), 4.41-4.26 (m, 4H), 4.00-3081 (m, 1H), 3.60-3.45 (m,2H), 3.42-3.22 (m, 1H), 2.82 (s, 3H), 2.43 (s, 3H), 1.64 (td, J=7.4,14.6 Hz, 1H), 1.46-1.36 (m, 1H), 1.24 (d, J=6.8 Hz, 3H), 1.13-0.99 (m,3H)

Example 43(R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, formic acid salt

A mixture of (R)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(200 mg, 0.518 mmol) in acetonitrile (3 mL), DIEA (0.272 mL, 1.555 mmol)and (R)-2-ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepinehydrochloride (134 mg, 0.622 mmol) was heated with μwave at 120° C. for1 h. The solvent was concentrated and the resulting residue was purifiedby silica gel chromatography. Desired fractions were concentrated andthe resulting intermediate was re-dissolved in MeOH (3 mL). 2 M LiOH(1.555 mL, 3.11 mmol) was added and the reaction mixture was stirred atambient temperature for 20 h. It was acidified with 6N HCl and 0.5 mLDMSO was added. It was concentrated and purified by reverse-phase HPLCto give the title compound (135 mg, 0.270 mmol, 52.1% yield) as solid.LC-MS m/z 500.3 (M+H)⁺, 0.78 min (ret. time).

Example 443-(3-((2,3-Dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid, formic acid salt

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(70 mg, 0.184 mmol) in Dichloromethane (DCM) (2 mL) was added thionylchloride (0.027 mL, 0.367 mmol). The mixture was stirred at ambienttemperature for 40 min. The solvent was concentrated and the resultingresidue was re-dissolved in acetonitrile (2 mL) afterwhich2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (36.7 mg, 0.246 mmol) and DIEA(0.095 mL, 0.543 mmol) were added. The resulting reaction mixture washeated with microwave at 120° C. for 1 h. The resulting mixture wasconcentrated and the resulting residue was re-dissolved in MeOH (2 mL),2 M LiOH (0.551 mL, 1.101 mmol) was added and the reaction mixture washeated with μwave at 80° C. for 30 min. It was acidified with 6N HCl and0.5 mL DMSO was added. It was concentrated and purified by reverse-phaseHPLC to give the title compound (21.8 mg, 0.044 mmol, 23.83% yield) assolid. LC-MS m/z 500.4 (M+H)⁺, 0.75 min (ret. time).

Example 453-(3-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt

Methyl3-(3-(hydroxymethyl)-4-methylphenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a suspension of (3-(hydroxymethyl)-4-methylphenyl)boronic acid (152mg, 0.919 mmol), (E)-methyl3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (200mg, 0.765 mmol), and chloro(1,5-cyclooctadiene)rhodium(I) dimer (37.7mg, 0.077 mmol) in water (1 mL) and 1,4-dioxane (3 mL) at ambienttemperature was added triethylamine (0.320 mL, 2.296 mmol). Theresulting suspension was heated to 95° C. for 2 h. It was filteredthrough celite and washed with ethyl acetate. The filtrate wasconcentrated. The crude product was purified by reverse-phase HPLC togive the title compound (109 mg, 0.284 mmol, 37.1% yield). LC-MS m/z384.2 (M+H)⁺, 0.85 min (ret. time).

Methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of methyl3-(3-(hydroxymethyl)-4-methylphenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(109 mg, 0.284 mmol) in dichloromethane (DCM) (2 mL) was added SOCl₂(0.041 mL, 0.569 mmol). The resulting reaction mixture was stirred atambient temperature for 1 h. The solvent was removed to afford desiredproduct (98 mg, 0.244 mmol, 86% yield). LC/MS: m/z 402.0 (M+H)⁺, 1.15min (ret. time).

3-(3-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt

A mixture of methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(52 mg, 0.129 mmol),(R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (27.5 mg, 0.155mmol), and DIEA (0.068 mL, 0.388 mmol) in acetonitrile (2 mL) was heatedin a Biotage microwave at high absorption for 1 h at 120° C. The solventwas removed under reduced pressure and the crude material wasre-dissolved in MeOH (2 mL) and 2M LiOH (0.388 mL, 0.776 mmol) was addedand the reaction mixture was heated with microwave at 80° C. for 30 min.It was acidified with 6N HCl and 0.5 mL DMSO was added. It wasconcentrated and purified by reverse-phase HPLC (with 0.1% formic acidcondition) to give the title compound (55 mg, 0.096 mmol, 74.0% yield)as solid. LC-MS m/z 529.2 (M+H)⁺, 0.86 min (ret. time).

The compounds in Table 9 were prepared by a method similar to the onedescribed for the preparation of3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, Formic acid salt. As is appreciated by those skilled in the art,these analogous examples may involve variations in general reactionconditions.

TABLE 9 LCMS Retention Ex # Structure Name [M + H]⁺ Time (min) Example46

3-(3-((2-Ethyl-2,3- dihydrobenzo[f][1,4] oxazepin-4(5H)-yl) methyl)-4-methylphenyl)-3- (7-methoxy-1- methyl-1H-benzo[d] [1,2,3]triazol-5-yl)propanoic acid, trifluoroacetic acid salt 515.3 0.81

Example 473-(3,7-Dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, trifluoroacetic acid salt

5-Bromo-N2,4-dimethylpyridine-2,3-diamine

To a solution of 5-bromo-N,4-dimethyl-3-nitropyridin-2-amine (2000 mg,8.13 mmol) in ethanol (20 mL) at ambient temperature was added tin(II)chloride dihydrate (7336 mg, 32.5 mmol). The reaction mixture was heatedat 70° C. for the 2 h. Solvent was evaporated and NaHCO₃ (sat.) solutionwas added to pH 7. It was extracted with EtOAc (3×40 mL). The combinedorganic phase was dried with Na₂SO₄, filtered and concentrated to givethe title compound (1.53 g, 7.08 mmol, 87% yield) as brown solid. LC-MSm/z 215.9 (M+H)⁺, 0.41 min (ret. time).

6-Bromo-3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridine

To a solution of 5-bromo-N2,4-dimethylpyridine-2,3-diamine (1500 mg,6.94 mmol) in sulfuric acid (18.500 mL, 34.7 mmol) at ambienttemperature, sodium nitrite (479 mg, 6.94 mmol) was added. The reactionmixture was heated at 70° C. for 1 h. The reaction mixture was cooledand extracted with EtOAc and water. The water layer was extracted withEtOAc (2×30 mL). The combined organic phase was dried and concentratedto afford the title compound (1500 mg, 6.61 mmol, 95% yield) as brownsolid. LC-MS m/z 226.9 (M)⁺, 0.71 min (ret. time).

(E)-Methyl3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)acrylate

To a solution of 6-bromo-3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridine(800 mg, 3.52 mmol) in N,N-dimethylformamide (DMF) (5 mL) at ambienttemperature was added methyl acrylate (1.612 mL, 17.62 mmol) andN-ethyl-N-isopropylpropan-2-amine (2.154 mL, 12.33 mmol),tri-o-tolylphosphine (322 mg, 1.057 mmol), followed by palladium(II)acetate (103 mg, 0.458 mmol). The reaction mixture was heated inmicrowave under high absorption at 150° C. for 1 h. It was concentratedand the crude material was purified by silica gel chromatography. Thedesired fractions were concentrated under reduced pressure to give thetitle compound (279 mg, 1.201 mmol, 34.1% yield) and less pure batch(250 mg, 1.076 mmol, 30.6% yield). LC-MS m/z 233.0 (M+H)⁺, 0.68 min(ret. time).

Methyl3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

To a suspension of (3-(hydroxymethyl)-4-methylphenyl)boronic acid (214mg, 1.292 mmol), (E)-methyl3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)acrylate (250 mg,1.076 mmol), and chloro(1,5-cyclooctadiene)rhodium(I) dimer (53.1 mg,0.108 mmol) in water (1 mL) and 1,4-dioxane (3 mL) at ambienttemperature was added triethylamine (0.450 mL, 3.23 mmol). The resultingsuspension was heated to 95° C. for 1 h. It was concentrated and thecrude product was purified by silica gel chromatography. The desiredfractions were concentrated to give the title compound (353 mg, 0.996mmol, 93% yield) as oil. LC-MS m/z 355.3 (M+H)⁺, 0.74 min (ret. time).

3-(3,7-Dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, trifluoroacetic acid salt

To a solution of methyl3-(3-ethyl-7-methyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(80 mg, 0.226 mmol) in dichloromethane (DCM) (2.000 mL) was addedthionyl chloride (0.033 mL, 0.451 mmol). The reaction mixture wasstirred at ambient temperature for 1 h. It was concentrated andre-dissolved in acetonitrile (2 mL).(R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine, hydrochloride(55.89 mg, 0.271 mmol) and DIEA (0.118 mL, 0.677 mmol) were added. Thereaction mixture was heated in a Biotage microwave at high absorptionfor 1 h at 120° C. It was concentrated and re-dissolved in 1 mL MeOH. 2MLiOH (0.651 mL, 1.303 mmol) was added and heated in a Biotage microwaveat high absorption for 30 min at 80° C. It was acidified with 6N HCl and0.5 mL DMSO was added. It was concentrated and purified by reverse-phaseHPLC (with 0.1% TFA condition) to give the title compound (79.6 mg,71.1%) as clear oil. LC-MS m/z 500.3 (M+H)⁺, 0.77 min (ret. time).

Example 483-(3,7-Dimethyl-3H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, trifluoroacetic acid salt

Ethyl3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

To a suspension of (3-(hydroxymethyl)-4-methylphenyl)boronic acid (8.09mg, 0.049 mmol), (E)-ethyl3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)acrylate (10 mg,0.041 mmol), and chloro(1,5-cyclooctadiene)rhodium(I) dimer (2.002 mg,4.06 μmol) in water (1 mL) and 1,4-dioxane (3 mL) at ambient temperaturewas added triethylamine (0.017 mL, 0.122 mmol). The resulting suspensionwas heated to 95° C. for 2 h. It was filtered though celite and washedwith ethyl acetate. The filtrate was concentrated. The crude product waspurified by reverse-phase HPLC to give the title compound (3 mg, 8.14μmol, 20.05% yield). LC-MS m/z 369.2 (M+H)⁺, 0.85 min (ret. time).

3-(3,7-Dimethyl-3H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, trifluoroacetic acid salt

To a solution of ethyl3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(3 mg, 8.14 μmol) in dichloromethane (DCM) (1.000 mL) was added thionylchloride (0.594 μL, 8.14 μmol). The mixture was stirred for 1 h atambient temperature. It was concentrated and re-dissolved inacetonitrile (1 mL).(R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine, hydrochloride(2.088 mg, 9.77 μmol) and DIEA (4.27 μL, 0.024 mmol) were added. Thereaction mixture was heated in a Biotage microwave at high absorptionfor 1 h at 120° C. It was concentrated and re-dissolved in 1 mL MeOH. 2MLiOH (0.024 mL, 0.049 mmol) was added and heated in a Biotage microwaveat high absorption for 30 min at 80° C. It was acidified with 6N HCl and0.5 mL DMSO was added. It was concentrated and purified by reverse-phaseHPLC to give the title compound (2.6 mg, 0.052 mmol, 55%) as solid.LC-MS m/z 500.4 (M+H)⁺, 0.76 min (ret. time).

Example 49(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, formic acid salt

(S)-Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoateand (R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (950 mg, 2.59 mmol) was purified with chiral SFC (Column:Chiralpak AD, 20×250 mm, 5 u; Co-solvent: 30% MeOH; Flow rate: 50 g/min;Back Pressure: 100 bar to give single enantiomerically pure (S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(475 mg, 1.293 mmol, 50.0% yield) (chiral SFC ret. time: 2.7 min) andsingle enantiomerically pure (R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(481 mg, 1.309 mmol, 50.6% yield) (chiral SFC ret. time: 3.41 min) asoil.

(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, formic acid salt

To a solution of (S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(60 mg, 0.163 mmol) in dichloromethane (DCM) (2 mL) was added thionylchloride (0.024 mL, 0.327 mmol). The mixture was stirred at ambienttemperature for 1 h. The solvent was removed under reduced pressure andthe residue re-dissolved in acetonitrile (2 mL).(R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine, hydrochloride(52.3 mg, 0.245 mmol) and DIEA (0.114 mL, 0.653 mmol) were added. Theresulting reaction mixture was heated with microwave at 120° C. for 1 h.The reaction mixture was concentrated to give (S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate.It was re-dissolved in methanol (2 mL) and 2M LiOH (0.490 mL, 0.980mmol) was added. The resulting reaction mixture was heated withmicrowave at 80° C. for 30 min. It was quenched with 6N HCl and 0.5 mLDMSO was added. The solvent was removed under reduced pressure and theresidue purified by reverse-phase HPLC (with 0.1% formic acid condition)to give the title compound (66.7 mg, 0.128 mmol, 78% yield). LC-MS m/z499.5 (M+H)⁺, 0.79 min (ret. time).

The compounds in Table 10 were prepared by a method similar to the onedescribed for the preparation of(S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid. As is appreciated by those skilled in the art, these analogousexamples may involve variations in general reaction conditions.

TABLE 10 LCMS Retention Ex # Structure Name [M + H]⁺ Time (min) Example50

(S)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3- dihydropyrido[3,4- f][1,4]oxazepin-4(5H)-yl)methyl)-4- methylphenyl)propanoic acid, formic acid salt 500.4 0.72Example 51

(R)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)- 4-methylphenyl)propanoic acid, formic acidsalt 499.4 0.79 Example 52

(S)-3-(1-Ethyl-4-fluoro-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9- fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) methyl)-4-methylphenyl) propanoic acid, 0.5formic acid salt 535.6 0.86 Example 53

(S)-3-(3-(((R)-2-Ethyl-2,3- dihydropyrido[3,4- f][1,4]oxazepin-4(5H)-yl)methyl)-4- methylphenyl)-3-(1-ethyl- 4-fluoro-1H-benzo[d][1,2,3]triazol-5- yl)propanoic acid 518.3 0.89 Example 54

(S)-3-(4-Chloro-1-ethyl- 1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl- 2,3-dihydrobenzo[f][1,4] oxazepin-4(5H)-yl)methyl)-4-methylphenyl) propanoic acid, hydrochloride 533.2 0.86 Example55

(R)-3-(4-Chloro-1-ethyl- 1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl- 2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)- 4-methylphenyl)propanoate, Sodium salt 533.20.87 Example 56

(S)-3-(4-Chloro-1-ethyl- 1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl- 2,3-dihydrobenzo[f] [1,4]oxazepin-4(5H)-yl)methyl)-4- methylphenyl)propanoic acid 533.3 0.84 Example 57

(R)-3-(1,4-Dimethyl-1 H- benzo[d][1,2,3]triazol-5-yl)-3-(3-((7-fluoro-2,2- dimethyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) methyl)-4-methylphenyl) propanoic acid, 0.7 formicacid salt 517.4 0.90 Example 58

(S)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9- fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)- yl)methyl)-4- methylphenyl)propanoic acid,Sodium salt 517.2 0.86 Example 59

(R)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-((8-fluoro-2,2- dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)- yl)methyl)-4- methylphenyl)propanoic acid 517.40.96 Example 60

(R)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9- fluoro-2,3-dihydrobenzo-[f][1,4]oxazepin-4(5H)- yl)methyl)-4-methyl- phenyl)propanoic acid,Sodium salt 517.5 0.83 Example 61

(R)-3-(4-Chloro-1-ethyl- 1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl- 2,3-dihydrobenzo[f][1,4] oxazepin-4(5H)-yl)methyl)-4-methylphenyl) propanoic acid 533.2 0.88 Example 62

(S)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-((7-fluoro-2,2- dimethyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) methyl)-4-methylphenyl) propanoic acid, 1.5 formicacid salt 517.5 0.89 Example 63

(S)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3[triazol-5-yl)-3-(3-((8-fluoro-2,2- dimethyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) methyl)-4-methylphenyl) propanoic acid 517.4 0.93

Example 64(S)-3-(3-((2,2-Dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

To a solution of benzyl3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(460 mg, 1.028 mmol) in dichloromethane (5 mL) was added thionylchloride (0.150 mL, 2.056 mmol). The mixture was stirred for 40 min thenconcentrated and the residue re-dissolved in acetonitrile (5 mL).2,2-Dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride (264mg, 1.234 mmol) was added. The mixture was heated via microwave at 120°C. for 1 h. The resulting mixture was concentrated then re-dissolved inMeOH (3 mL). 2 M LiOH (3.60 mL, 7.20 mmol) was added and the reactionstirred at 60° C. for 4 h. The reaction was acidified with 6N HCl and0.5 mL DMSO was added. The resulting mixture was concentrated, filteredand purified with preparative HPLC under acidic conditions (with 0.1%TFA as modifier) to give racemic compound. This was resolved by ChiralSFC (Column: Chiralpak OJ 20×250 mm, 5 u; Co-solvent: 20% IPA; Flowrate:50 g/min; Back pressure: 100 Bar) to give single enantiomerically pure(S)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (229.8 mg) (chiral SFC ret. time: 6.11 min) LC-MS m/z 517.4 (M+H)⁺,0.86 min (ret. time) and single enantiomerically pure(R)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (250 mg) (chiral SFC ret. time: 7.22 min). However, a littlemethanol was used after chiral separation for(R)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid which resulted to form a mixture of (R)-methyl3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoateand(R)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (250 mg). LC-MS m/z 517.3 (M+H)⁺, 0.85 min (ret. time). LC-MS m/z531.1 (M+H)⁺, 0.96 min (ret. time)

Example 65(R)-3-(3-((2,2-Dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, Hydrochloride

To a solution of (R)-methyl3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoateand(R)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (250 mg, 0.471 mmol) in methanol (5 mL) was added 2 M LiOH (1.413mL, 2.83 mmol). The mixture was stirred at ambient temperature for 18 h.The resulting mixture was concentrated then acidified with 6N HCl topH-, and then extracted with ethyl acetate twice. The organic layer wasdried with sodium sulfate, filtered and concentrated to give the titlecompound (193 mg, 0.349 mmol, 74.1% yield). LC-MS m/z 517.4 (M+H)⁺, 0.89min (ret. time)

(S)-Benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoateand (R)-benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate

To a suspension of(R)-2-ethyl-4-(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(626 mg, 1.536 mmol), (E)-benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (500 mg,1.463 mmol), and [RhCl(cod)]₂ (72.1 mg, 0.146 mmol) in dioxane (8 mL)and water (2 mL) at ambient temperature was added triethylamine (0.612mL, 4.39 mmol). The resulting suspension was heated at 90° C. for 1 h.The reaction mixture was passed through celite and washed with EtOAc.The organic layer was collected and concentrated to give the crudeproduct. The crude product was purified by silica gel chromatography thetitle intermediate benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate(300 mg, 0.481 mmol, 32.9% yield) and a less pure batch (210 mg). Bothbatches were resolved by Chiral SFC (Chiralpak IF 20×250 mm, 5 u;Co-solvent: 30% EtOH; Flowrate: 50 g/min; Back pressure: 100 Bar) togive single enantiomerically pure (S)-benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate(190 mg, 0.305 mmol, 20.84% yield) (chiral SFC ret. time: 6.37 min)LC-MS m/z 623.4 (M+H)⁺, 1.06 min (ret. time) and single enantiomericallypure (R)-benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate(204 mg, 0.327 mmol, 22.38% yield) (chiral SFC ret. time: 7.62 min)LC-MS m/z 623.4 (M+H)⁺, 1.06 min (ret. time)

Example 66(S)-3-(4-Chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate,Sodium

To a solution of (S)-benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate(190 mg, 0.305 mmol) in methanol (8 mL) at 25° C. was added 2 M LiOH(0.915 mL, 1.829 mmol). The reaction mixture was stirred at ambienttemperature for 20 h. The reaction was acidified with 6N HCl to pH 1, 1mL DMSO was added and the mixture concentrated. The crude material waspurified by reverse phase preparative HPLC using 0.1% TFA as a solventmodifier. Desired product fractions were concentrated then re-dissolvedin ethyl acetate, extracted with saturated sodium bicarbonate. Theorganic layer was washed with brine, dried over sodium sulfate, filteredand concentrated to give the title compound (80 mg, 0.144 mmol, 47.3%yield) as solid. LC-MS m/z 533.2 (M+H)⁺, 0.88 min (ret. time)

Example 67(R)-3-(4-Chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate,Sodium

To a solution of (R)-benzyl3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate(204 mg, 0.327 mmol) in methanol (8 mL) at 25° C. was added 2 M LiOH(0.982 mL, 1.964 mmol). The reaction mixture was stirred at ambienttemperature for 20 h. The reaction was acidified with 6N HCl to pH 1, 1mL DMSO was added and the mixture concentrated. The crude material waspurified by reverse phase preparative HPLC using 0.1% TFA as a solventmodifier. The desired product was re-dissolved in ethyl acetate andextracted with saturated sodium bicarbonate. The organic layer waswashed with brine, dried over sodium sulfate, filtered and concentratedto give the title compound (106 mg, 0.191 mmol, 58.3% yield) as solid.LC-MS m/z 533.2 (M+H)⁺, 0.90 min (ret. time)

Example 68(S)-3-(3-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt

(S)-Ethyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoateand (R)-ethyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

Ethyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (390 mg, 1.022 mmol) was separated by Chiral SFC method(Column: Chiralpak AY, 20×250 mm, 5 u; Co-solvent: 20% EtOH; Flow rate:55 g/min; Back Pressure: 100 bar) to give single enantiomerically pure(S)-ethyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(139 mg) (chiral SFC ret. time: 2.71 min) LC-MS m/z 382.2 (M+H)⁺, 0.91min (ret. time) and single enantiomerically pure (R)-ethyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(151 mg) (chiral SFC ret. time: 4.18 min) LC-MS m/z 382.3 (M+H)⁺, 0.92min (ret. time).

(S)-3-(3-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt

A mixture of (S)-ethyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(50 mg, 0.131 mmol),(R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (27.9 mg, 0.157mmol), and DIEA (0.069 mL, 0.393 mmol) in acetonitrile (2 mL) was heatedin a Biotage microwave at high absorption for 1 h at 120° C. The solventwas removed under reduced pressure and the crude material wasre-dissolved in MeOH (2 mL) and 2M LiOH (0.393 mL, 0.786 mmol) was addedand the reaction mixture was heated with microwave at 80° C. for 30 min.It was acidified with 6N HCl and 0.5 mL DMSO was added. It wasconcentrated and purified by reverse-phase HPLC to give the titlecompound (40.3 mg, 0.079 mmol, 60.0% yield) as solid. LC-MS m/z 513.4(M+H)+, 0.83 min (ret. time).

Example 693-(3-((2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt

Ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To ethyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (120 mg, 0.315 mmol) in dichloromethane (DCM) (2 mL) wasadded SOCl₂ (0.046 mL, 0.629 mmol). The resulting reaction mixture wasstirred at ambient temperature for 1 h. The solvent was removed to givethe title compound (126 mg, 0.315 mmol, 100% yield). LC/MS m/z 399.9(M+H)⁺, 1.14 min (ret. time).

3-(3-((2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt

To methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(70 mg, 0.181 mmol) in acetonitrile (2 mL) was added2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (0.056 mL, 0.272 mmol)and DIEA (0.095 mL, 0.544 mmol). The resulting reaction mixture washeated with μwave at 120° C. for 1 h. The solvent was removed underreduced pressure and the residue re-dissolved in MeOH (2 mL). 2M LiOH(0.544 mL, 1.088 mmol) was added. It was heated with microwave at 80° C.for 60 min. It was quenched with 6N HCl and 0.5 mL DMSO was added. Thesolvent was removed under reduced pressure and the residue purified byreverse-phase HPLC (with 0.1% formic acid condition) to give the titlecompound (52 mg, 0.093 mmol, 51.3% yield) as solid. LC-MS m/z 513.5(M+H)⁺, 0.83 min (ret. time).

Example 703-(3-((2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt

To methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(70 mg, 0.174 mmol) in acetonitrile (6 mL) were added2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (0.054 mL, 0.261 mmol)and DIEA (0.091 mL, 0.523 mmol). The resulting reaction mixture washeated with microwave at 120° C. for 1 h. The reaction mixture wasconcentrated to give methyl3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate.It was re-dissolved in methanol (2 mL) and 2M LiOH (0.523 mL, 1.045mmol) was added. The resulting reaction mixture was heated withmicrowave at 80° C. for 60 min. It was quenched with 6N HCl and 0.5 mLDMSO was added. The solvent was removed under reduced pressure and theresidue purified by reverse-phase HPLC (with 0.1% formic acid condition)to give the title compound (65 mg, 0.113 mmol, 64.9% yield) wasobtained. LC-MS m/z 529.2 (M+H)⁺, 0.82 min (ret. time).

Example 713-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-propyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid, formic acid salt

To ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(80 mg, 0.207 mmol) in acetonitrile (2 mL) were added2-propyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (59.5 mg, 0.311 mmol)and DIEA (0.109 mL, 0.622 mmol). The resulting reaction mixture washeated with microwave at 120° C. for 1.5 h. The solvent was removedunder reduced pressure and the crude material was re-dissolved in MeOH(2 mL) and 2M LiOH (0.622 mL, 1.244 mmol) was added and the reactionmixture was heated with microwave at 80° C. for 30 min. It was acidifiedwith 6N HCl and 0.5 mL DMSO was added. It was concentrated and purifiedby reverse-phase HPLC to give the title compound (55.7 mg, 0.100 mmol,48.1% yield) as solid. LC-MS m/z 513.3 (M+H)⁺, 0.87 min (ret. time).

The compounds in Table 11 were prepared by a method similar to the onedescribed for the preparation of3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-propyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid, formic acid salt. As is appreciated by those skilled in the art,these analogous examples may involve variations in general reactionconditions.

TABLE 11 LCMS Retention Ex # Structure Name [M + H]⁺ Time (min) Example72

3-(1,4-dimethyl-1H- benzo[d][1,2,3]triazol-5- yl)-3-(3-((2-isopropyl-2,3-dihydrobenzo[f] [1,4]oxazepin-4(5H)- yl)methyl)-4-methylphenyl)propanoic acid, formic acid salt 513.6 0.84 Example 73

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3- dihydrobenzo[f][1,4] oxazepin-4(5H)-yl)methyl)-4- methylphenyl)propanoic acid, formic acid salt 499.2 0.81Example 74

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5- yl)-3-(3-((2-(methoxymethyl)-2,3- dihydrobenzo[f][1,4] oxazepin-4(5H)-yl) methyl)-4-methylphenyl)propanoic acid, formic acid salt 515.2 0.74

Example 753-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, formic acid salt

Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate

To a solution of(R)-2-ethyl-8-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (152 mg,0.777 mmol) and ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1Hbenzo[d][1,2,3]triazol-5-yl)propanoate(150 mg, 0.389 mmol) in acetonitrile (6 mL) was added DIPEA (0.136 mL,0.777 mmol) at ambient temperature. The reaction mixture was stirred inmicrowave reactor at 90° C. for 1 h. The reaction mixture was cooled to0° C., quenched with cold water, extracted twice with EtOAc followed bybrine solution. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated. It was purified by silica gel chromatographyto give the title compound (180 mg, 0.330 mmol, 85% yield) as liquid.LC-MS m/z 545.42 (M+H)⁺, 2.16 min (ret. time).

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, formic acid salt

To a solution of ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate(180 mg, 0.330 mmol) in ethanol (10 mL) was added 10% NaOH (10 mL, 0.330mmol) at 0° C. The reaction was stirred at ambient temperature for 16 h.The reaction mixture was evaporated under reduced pressure, neutralizedwith 2N HCl, extracted with twice DCM followed by brine solution. Theorganic layer was dried (Na₂SO₄), filtered and purified by reverse-phaseHPLC to give the title compound (80 mg, 0.154 mmol, 46.7% yield) aswhite solid. LC-MS m/z 517.36 (M+H)⁺, 1.90 min (ret. time).

The compounds in Table 12 were prepared by a method similar to the onedescribed for the preparation of3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, formic acid salt. As is appreciated by those skilled in the art,these analogous examples may involve variations in general reactionconditions.

TABLE 12 LCMS Retention Ex # Structure Name [M + H]⁺ Time (min) Example76

Ammonium 3-(1,4- Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2- ethyl-9-methyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) methyl)-4- methylphenyl)propanate 513.42 1.90 Example77

Ammonium 3-(3-(((R)- 7-Chloro-2-ethyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) methyl)-4- methylphenyl)-3- (1,4-dimethyl-1H-benzo[d][1,2,3] triazol-5-yl)propanate 533.36 2.03 Example 78

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-3-(3-(((R)-2-ethyl-7-fluoro-2,3- dihydrobenzo[f][1,4] oxazepin-4(5H)-yl)methyl)-4-methylphenyl) propanoic acid, formic acid salt 517.36 1.91Example 79

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3- f][1,4]oxazepin-4(5H)- yl)methyl)-4-methylphenyl) propanoic acid 500.19 1.70 Example 80

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-3-(3-(((R)-2-ethyl-9-fluoro-2,3- dihydrobenzo[f][1,4] oxazepin-4(5H)-yl) methyl)-4-methylphenyl)propanoic acid, formic acid salt 517.36 1.93 Example 81

Ammonium 3-(1,4- dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl- 7-methyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) methyl)-4- methylphenyl)propanate 513.42 1.88 Example82

3-(3-((8-Bromo-2-ethyl- 2,3-dihydrobenzo- [f][1,4]oxazepin-4(5H)-yl)methyl)-4-methyl- phenyl)-3-(1,4-dimethyl- 1H-benzo[d]- [1,2,3]triazol-5-yl)propanoic acid 577.0 3.30 Example 83

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-3-(3-(((R)-2-ethyl-6-fluoro-2,3- dihydrobenzo[f][1,4] oxazepin-4(5H)-yl) methyl)-4-methylphenyl) propanoic acid 517.32 1.95 Example 84

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-3-(3-((2-ethyl-8-methoxy-2,3- dihydrobenzo[f][1,4] oxazepin-4(5H)-yl) methyl)-4-methylphenyl)propanoic acid, formic acid salt 529.35 1.83 Example 85

Ammonium 3-(1,4- Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2- ethyl-8-methyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) methyl)-4- methylphenyl) propanoate 513.42 1.92Example 86

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-3-(3-(((R)-2-ethyl-2,3- dihydropyrido[3,4- f][1,4]oxazepin-4(5H)- yl)methyl)-4-methylphenyl) propanoic acid 500.41 1.66 Example 87

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-3-(3-((2-ethyl-7-fluoro-2,3- dihydrobenzo[f][1,4] oxazepin-4(5H)-yl) methyl)-4-methylphenyl) propanoic acid 517.39 3.37 Example 88

3-(3-((6-Chloro-2-ethyl- 2,3-dihydrobenzo[f] [1,4]oxazepin-4(5H)-yl)methyl)-4- methylphenyl)-3- (1,4-dimethyl-1 H-benzo[d][1,2,3]triazol- 5-yl)propanoic acid 533.23 3.48 Example 89

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-3-(3-((2,2-dimethyl-2,3- dihydrobenzo[f][1,4] oxazepin-4(5H)-yl) methyl)-4-methylphenyl) propanoic acid 499.25 1.85 Example 90

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-3-(3-(((R)-2-ethyl-2,3- dihydropyrido[4,3- f][1,4]oxazepin-4(5H)- yl)methyl)-4-methylphenyl) propanoic acid 500.1 3.10 Example 91

3-(3-(((R)-2-Ethyl-2,3- dihydrobenzo[f][1,4] oxazepin-4(5H)-yl)methyl)-4- methylphenyl)-3-(1- methyl-1H-benzo[d] [1,2,3]triazol-5-yl)propanoic acid 485.32 1.77 Example 92

3-(3-((6,7-Dihydro- 5H-imidazo[1,5- a][1,4]diazepin-8(9H)- yl)methyl)-4-methylphenyI)-3-(1,4- dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)propanoic acid, Sodium salt 459.3 0.68

Example 933-(3-(((S)-8-bromo-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt

(S)-8-bromo-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of (S)-1-aminopropan-2-ol (0.079 mL, 1.000 mmol) inmethanol (5 mL) was added 2,4-dibromobenzaldehyde (0.167 mL, 1 mmol).The resulting reaction mixture was stirred at ambient temperature for 20min. NaBH₄ (15.13 mg, 0.400 mmol) was added slowly. The resultingreaction mixture was stirred at ambient temperature for 20 min. afterwhich time it was evaporated under vacuum then was redissolved in DCM (5mL), dried over MgSO₄, filtered, and concentrated. This resultintermediate was dissolved in isopropanol (5.00 mL), copper(I) iodide(19.05 mg, 0.100 mmol) and K₂CO₃ (276 mg, 2.000 mmol) were added. Theresulting reaction mixture was heated with microwave at 100° C. for 30min. This reaction mixture was evaporated under vacuum, redissolved inDCM (5 mL), dried over MgSO₄, filtered, evaporated under vacuum toafford the product(S)-8-bromo-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (258.9 mg,1.069 mmol, 107% yield). LC-MS m/z 242.0 (M+H)⁺, 0.57 min (ret. time).

3-(3-(((S)-8-bromo-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt

To a solution of(S)-8-bromo-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (47.1 mg,0.194 mmol) in tetrahydrofuran (0.5 mL) and acetonitrile (1 mL) wereadded DIEA (0.091 mL, 0.518 mmol) and then a solution of ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(50 mg, 0.130 mmol) in acetonitrile (1 mL). The resulting reactionmixture was heated with microwave at 100° C. for 1 h. It wasconcentrated and redissolved in methanol (2 mL). NaOH (3.0 N) (0.346 mL,1.037 mmol) was added. The resulting reaction mixture was heated withmicrowave at 80° C. for 20 min. The reaction mixture was thenneutralized with HCl (2 N) to pH 6, evaporated under vacuum, purified byreverse phase HPLC to afford the desired product3-(3-(((S)-8-bromo-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt (12.1 mg, 0.021 mmol, 16.57% yield). LC-MS m/z563.2 (M+H)⁺, 0.85 min (ret. time).

Example 943-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((R)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid, formic acid salt

To a solution of ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(50 mg, 0.130 mmol) in acetonitrile (1.5 mL) were added(R)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine, hydrochloride(38.8 mg, 0.194 mmol), K₂CO₃ (53.7 mg, 0.389 mmol) and sodium iodide(3.88 mg, 0.026 mmol). The resulting reaction mixture was stirred at 40°C. for 67 h. The reaction mixture was filtered. The filter cake waswashed with MeCN (1 mL). The filtrate was concentrated. Thisintermediate was dissolved in methanol (1.5 mL), NaOH (3 N) (0.216 mL,0.648 mmol) was added. The resulting reaction mixture was heated withmicrowave at 80° C. for 20 min. The reaction mixture was acidified withHCl (3 N) to pH ˜6, evaporated under vacuum, purified by reverse phaseHPLC to afford desired product3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((R)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid, formic acid salt (47.0 mg, 0.091 mmol, 70.2% yield). LC-MS m/z485.5 (M+H)⁺, 0.70 min (ret. time).

Example 953-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-fluoro-3-(((S)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid, formic acid salt

(S)-1-((2-bromobenzyl)amino)propan-2-ol

To a solution of (S)-1-aminopropan-2-ol (0.236 mL, 3.00 mmol) inmethanol (10 mL) was added 2-bromobenzaldehyde (0.350 mL, 3 mmol). Theresulting reaction mixture was stirred at ambient temperature for 1 h.Then NaBH₄ (45.4 mg, 1.200 mmol) was added slowly. The resultingreaction mixture was stirred at ambient temperature for 66 h. Solventwas evaporated under vacuum. It was redissolved in DCM (5 mL), driedover MgSO₄, filtered, evaporated under vacuum to afford product(S)-1-((2-bromobenzyl)amino)propan-2-ol (710.7 mg, 2.91 mmol, 97%yield). LC-MS m/z 244.1 (M+H)⁺, 0.49 min (ret. time).

(S)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of (S)-1-((2-bromobenzyl)amino)propan-2-ol (580 mg, 2.376mmol) in isopropanol (10 mL) was added copper(I) iodide (45.2 mg, 0.238mmol) and K₂CO₃ (657 mg, 4.75 mmol). The result reaction mixture washeated with microwave at 130° C. under N₂ atmosphere for 1 h. Thereaction mixture was filtered. The filter cake was washed with i-PrOH (1mL). The combined filtrate was evaporated down under vacuum before wasredissolved in DCM (5 mL), dried over MgSO₄, filtered, evaporated downunder vacuum to afford product(S)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (393.3 mg, 2.410mmol, 101% yield). LC-MS m/z 164.1 (M+H)⁺, 0.49 min (ret. time).

Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-fluoro-3-(hydroxymethyl)phenyl)propanoate

To a solution of (E)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (490 mg, 1.998mmol) and(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(762 mg, 3.02 mmol) in 1,4-dioxane (9 mL) and water (6 mL) was addedchloro(1,5-cyclooctadiene)rhodium(I) dimer (65 mg, 0.132 mmol) and TEA(0.557 mL, 4.00 mmol). The mixture was heated in microwave at 100° C.for 1 h. The resulting mixture was filtered, water (10 mL) and ethylacetate were added. The layers were separated. The aquous layer wasextracted with ethyl acetate twice. The combined organic layer was driedover MgSO₄, filtered, concentrated and purified by silica gelchromatography to get 400 mg of ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-fluoro-3-(hydroxymethyl)phenyl)propanoate (53.9%). LC-MS m/z 372.2 (M+1)⁺, 0.84 (ret. time).

Ethyl3-(3-(chloromethyl)-4-fluorophenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-fluoro-3-(hydroxymethyl)phenyl)propanoate(100 mg, 0.269 mmol) in dichloromethane (1 mL) was added SOCl₂ (0.039mL, 0.538 mmol). The resulting reaction mixture was stirred at ambienttemperature for 1 h. Solvent was evaporated under vacuum to affordproduct ethyl3-(3-(chloromethyl)-4-fluorophenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(104 mg, 0.267 mmol, 99% yield). LC-MS m/z 390.0 (M+H)⁺, 1.70 min (ret.time).

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-fluoro-3-(((S)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid, formic acid salt

To a solution of ethyl3-(3-(chloromethyl)-4-fluorophenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(52 mg, 0.133 mmol) in acetonitrile (1 mL) were added Et₃N (0.037 mL,0.267 mmol) and (S)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(32.7 mg, 0.200 mmol). The result solution was heated with microwave at80° C. for 2 h. The solvent was removed and the residue was diluted inmethanol (1.5 mL) then was added NaOH (2 N) (26.7 mg, 0.667 mmol). Theresulting suspention was heated with microwave at 80° C. for 30 min. Thereaction mixture was acidified with AcOH (2 N) to pH ˜5, evaporatedunder vacuum, purified by reverse phase HPLC to afford product3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-fluoro-3-(((S)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid, formic acid salt (39.2 mg, 0.080 mmol, 60.2% yield). LC-MS m/z489.3 (M+H)⁺, 0.74 min (ret. time).

Example 963-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid

To a solution of ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(90 mg, 0.233 mmol) in acetonitrile (1 mL) was added2,2-dimethyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (49.9 mg,0.280 mmol). The resulting solution was heated with microwave at 80° C.for 30 min. The reaction mixture was concentrated. It was diluted withmethanol (1.5 mL) then was added NaOH (2 N) (46.6 mg, 1.166 mmol). Theresulting solution was heated with microwave at 80° C. for 30 min. Thereaction mixture was acidified with AcOH (2 N) to pH ˜5, evaporatedunder vacuum, purified by reverse phase HPLC to afford product3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid (78.7 mg, 0.158 mmol, 67.5% yield). LC-MS m/z 500.2 (M+H)⁺, 0.72min (ret. time).

Example 973-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((S)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid, formic acid salt

N-Ethyl-3-methyl-2-nitroaniline

To a solution of 2-fluoro-6-methylaniline (8.5 g, 67.9 mmol) in1,2-dichloroethane (DCE) (150 mL) at ambient temperature was addedm-CPBA (58.6 g, 272 mmol) slowly under nitrogen. The reaction mixturewas stirred at 70° C. for 4 h. DCM (500 mL) was added. It was washedwith 1N NaOH (200 mL×4). The combined organic layers was dried andconcentrated to give the crude product (11.2 g, 72.2 mmol). It wasdissolved in ethanol (80 mL), ethanamine (80 mL, 911 mmol) was addedslowly under nitrogen at ambient temperature. The reaction mixture wasstirred at 60° C. for 16 h. Water (100 mL) was added. It was extractedwith ethyl acetate (3×80 mL). The combined organic layers was dried andconcentrated. The crude product was purified by silica gelchromatography (hexane:ethyl acetate=100:1) to give 11.9 g (85%) of thetitle compound. LC-MS m/z 181.2 (M+H)⁺, 1.81(ret. time).

4-Bromo-N-ethyl-3-methyl-2-nitroaniline

To a solution of N-ethyl-3-methyl-2-nitroaniline (11.9 g, 66.0 mmol) inN,N-dimethylformamide (DMF) (100 mL) was added a solution of NBS (11.75g, 66.0 mmol) in 100 mL of DMF dropwise. Then the reaction mixture wasstirred at ambient temperature for 16 h. Water (800 mL) was added. Thesolid was filtered and dried to give 16 g (78%) of the title compound.LC-MS m/z 2.02 (M+H)⁺, 260.9 (ret. time).

4-Bromo-N1-ethyl-3-methylbenzene-1,2-diamine

To 4-bromo-N-ethyl-3-methyl-2-nitroaniline (16 g, 61.8 mmol) in aceticacid (100 mL) was added zinc (12.11 g, 185 mmol) in small portions. Thereaction mixture was stirred at ambient temperature for 10 h. Thereaction mixture was filtered through celite and the solid was washedwith EtOAc (3×). The combined organic was concentrated. The crudeproduct was purified by silica gel chromatography (hexane:ethylacetate=10:1) to give 4.0 g (16.96%) of the title compound. LC-MS m/z231.0 (M+H)⁺, 1.51 (ret. time).

5-Bromo-1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazole

To H₂SO₄ (1.954 mL, 36.7 mmol) in water (30 mL) was added4-bromo-N1-ethyl-3-methylbenzene-1,2-diamine (4 g, 10.48 mmol). Then asolution of sodium nitrite (1.445 g, 20.95 mmol) in water (20 mL) wasadded by dropwise at 0° C. The reaction mixture was stirred at 0° C. for16 h. Water (200 mL) was added. Solid was filtered. The solid was thendissolved in 500 mL of DCM, washed with aqueous NaCl (2×50 mL). Theorganic layer was dried with MgSO₄, filtered and concentrated to give2.4 g (76%) of the title compound. LC-MS m/z 242.0 (M+H)⁺, 1.80 (ret.time).

(E)-Ethyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate

To a solution of 5-bromo-1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazole(2.4 g, 7.00 mmol) in N,N-dimethylformamide (DMF) (100 mL) were addedtri-o-tolylphosphine (0.426 g, 1.399 mmol), ethyl acrylate (1.401 g,13.99 mmol) and DIPEA (3.67 mL, 20.99 mmol). Then Pd(OAc)₂ (0.157 g,0.700 mmol) was added. The reaction mixture was stirred at 100° C. for12 h. The reaction mixture was poured into water (30 mL) and extractedwith ethyl acetate (3×30 mL). The combined organic layers were dried andconcentrated. The crude product was purified by silica gelchromatography (hexane:ethyl acetate=4:1) to give 1.75 g (87%) of thetitle compound. LC-MS m/z 260.1 (M+H)⁺, 1.75(ret. time).

Ethyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

To the solution of (E)-ethyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (1 g, 3.86mmol) in 1,4-dioxane (30 mL) and water (10 ml) were added(3-(hydroxymethyl)-4-methylphenyl)boronic acid (1.280 g, 7.71 mmol),triethylamine (1.613 mL, 11.57 mmol) and then [RhCl(cod)]₂ (0.095 g,0.193 mmol). The resulting reaction mixture was stirred at 90° C. for 2h. The reaction mixture was extracted with EtOAc (3×30 mL). The combinedorganic layer was dried over MgSO₄, filtered, and concentrated underreduced pressure. It was purified by silica gel chromatography to affordthe desired product ethyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(1.3764 g, 3.61 mmol, 94% yield). LC-MS m/z 382 (M+H)⁺, 0.96 (ret.time).

Ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of ethyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(880 mg, 2.307 mmol) in dichloromethane (4 mL) was added SOCl₂ (0.337mL, 4.61 mmol). The resulting reaction mixture was stirred at ambienttemperature for 30 min. The reaction was evaporated under vacuum toafford the product ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate.LC-MS m/z 400.0 (M+H)⁺, 1.16 min (ret. time).

3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((S)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid, formic acid salt

To a solution of (S)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(30.6 mg, 0.188 mmol) in tetrahydrofuran (0.5 mL) and acetonitrile (1mL) was added DIEA (0.087 mL, 0.500 mmol) and then a solution of ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(50 mg, 0.125 mmol) in acetonitrile (1 mL). The resulting reactionmixture was heated with microwave at 100° C. for 1 h. The reactionmixture was concentrated. It was redissolved in methanol (2 mL), NaOH(3.0 N) (0.333 mL, 1.000 mmol) was added. The resulting reaction mixturewas heated with microwave at 80° C. for 20 min. It was neutralized withHCl (2 N) to pH 6, evaporated under vacuum, purified by reverse phaseHPLC to afford the desired product3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((S)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid, formic acid salt (51.6 mg, 0.103 mmol, 82% yield). LC-MS m/z 499.5(M+H)⁺, 0.76 min (ret. time).

Example 983-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((S)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid, formic acid salt

To a solution of (S)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(31.7 mg, 0.194 mmol) in tetrahydrofuran (0.5 mL) and acetonitrile (1mL) was added DIEA (0.091 mL, 0.518 mmol) and then a solution of ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(50 mg, 0.130 mmol) in acetonitrile (1 mL). The resulting reactionmixture was heated with microwave at 100° C. for 1 h. The reactionmixture was concentrated. It was redissolved in methanol (2 mL), NaOH(3.0 N) (0.346 mL, 1.037 mmol) was added. The resulting reaction mixturewas heated with microwave at 80° C. for 20 min then was neutralized withHCl (2 N) to pH 6, evaporated under vacuum, purified by reverse phaseHPLC to afford the product3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((S)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid, formic acid salt (48.2 mg, 0.099 mmol, 76% yield). LC-MS m/z 485.4(M+H)⁺, 0.70 min (ret. time).

Example 993-(4-Chloro-3-((2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt

To a solution of ethyl3-(4-chloro-3-(hydroxymethyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(70 mg, 0.180 mmol) in dichloromethane (0.5 mL) was added SOCl₂ (0.026mL, 0.361 mmol). The resulting reaction mixture was stirred at ambienttemperature for 3 h. The reaction mixture was evaporated under vacuum.It was diluted with acetonitrile (1 mL) followed by addition of Et₃N(0.050 mL, 0.361 mmol) and 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(32.3 mg, 0.217 mmol). The resulting mixture was heated with microwaveat 80° C. for 30 min. Solvent was removed and the residue was dilutedwith methanol (1.5 mL) followed by addition of NaOH (2N) (36.1 mg, 0.902mmol). The resulting suspension was heated with microwave at 80° C. for30 min. The reaction mixture was acidified with AcOH (2 N) to pH ˜5,evaporated under vacuum, purified by reverse phase HPLC to afford theproduct3-(4-chloro-3-((2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt (78.3 mg, 0.159 mmol, 88% yield). LC-MS m/z 500.2(M+H)⁺, 0.72 min (ret. time).

Example 100(3S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid

(S)-Ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of (S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(720 mg, 1.959 mmol) in dichloromethane (DCM) (10 mL) was added thionylchloride (0.172 mL, 2.351 mmol) and one drop DMF. The reaction mixturewas stirred at ambient temperature for 1 h. The solvent was removedunder reduced pressure to give the title compound (S)-Ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(700 mg, 1.778 mol, 91% yield). LC-MS m/z 386.1 (M+H)+, 2.05 min (ret.time).

(3S)-Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate

To a solution of (S)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(530 mg, 1.373 mmol) in acetonitrile (20 mL) were added2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (219 mg, 1.236 mmol)and potassium carbonate (380 mg, 2.75 mmol). The reaction mixture wasstirred at ambient temperature for 16 h. The reaction mixture wasquenched with H₂O (15 mL) and extracted with EtOAc (3×50 mL). Theorganic phase was washed with saturated brine (50 mL), dried over sodiumsulfate and concentrated to give the title compound (3S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate(500 mg, 0.665 mmol, 48.4% yield) as a brown solid. LC-MS m/z 527.3(M+H)⁺, 1.44 min (ret. time).

(3S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoate

To a solution of (3S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate(200 mg, 0.380 mmol) in tetrahydrofuran (THF) (5 mL) at −78° C., (1.899mL, 1.899 mmol, 1.0M solution in THF) was added. The wine red solutionwas stirred at −78° C. (dry-ice acetone) for 45 min and MeI (0.119 mL,1.899 mmol) was added in one portion. The red wine color was turned tolight yellow. The reaction mixture was stirred at −78° C. for a further45 min. The reaction was diluted with EtOAc (75 mL) and water (25 mL).The aqueous layer was extracted again with EtOAc (25 mL) and thecombined organics washed with brine (25 mL), dried over Na₂SO₄ andconcentrated to obtain the title compound (3S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydhydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoate(180 mg, 8.58 mmol, 0.280 mmol, 73.6% yield) which was carried to thenext step without further purification. LC-MS m/z 541.3 (M+H)⁺, 1.51 min(ret. time).

(3S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid

To a solution of (3S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoate(25 mg, 0.046 mmol) in a mixture of tetrahydrofuran (THF) (5mL)/methanol (1 mL) was added LiOH (5.54 mg, 0.231 mmol) in water (2.0mL). The reaction mixture was stirred at 60° C. for 24 h. Then theorganic solvent was evaporated and the residue was adjusted to pH 5 withHCl (3M, 1.5 mL). The solid was filtered, washed with H₂O (10 mL) andEt₂O (10 mL) to give the title compound(3S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid (100 mg, 0.195 mmol, 58.6% yield) as a yellow solid. LC-MS m/z513.2 (M+H)⁺, 1.56 min (ret. time).

Example 101 Ammonium(2S,3R)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanate

(R)-Ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of (R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(800 mg, 2.177 mmol) in dichloromethane (DCM) (15 mL) at 0° C.,imidazole (296 mg, 4.35 mmol), DMAP (13.30 mg, 0.109 mmol) andtert-butylchlorodimethylsilane (492 mg, 3.27 mmol) were added. Thereaction mixture was stirred at 0° C. to 25° C. for 2 h. The reactionmixture was quenched with water (10 mL), and extracted with DCM (3×20mL). The combined organic layer was washed with water (2×8 mL) and brine(2×8 mL), dried over Na₂SO₄ and concentrated. The residue was purifiedwith silica gel chromatography (petroleum ether/ethyl acetate=95:5) toobtain the title compound (R)-ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(1 g, 2.076 mmol, 95% yield) as yellow oil. LC-MS m/z 482.2 (M+H)⁺, 1.98(ret. time).

(3R)-Ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoateand (3R)-ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate

A solution of (R)-ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(1 g, 2.076 mmol) in tetrahydrofuran (THF) (20 mL) was added to asolution of dry-ice acetone bath cooled LDA (4.15 mL, 4.15 mmol, 1.0Msolution in THF). The wine red solution was stirred at −78° C. for 45min and MeI (0.26 mL, 4.15 mmol) was added in one portion and the redwine color was turned to light yellow. The reaction mixture was stirredat −78° C. for an additional 45 min. The residue was diluted with EtOAc(100 mL) and water (25 mL). The aqueous layer was extracted with EtOAc(3×50 mL) and the combined organic layer was washed with brine (25 mL),dried over Na₂SO₄ and concentrated to give the title compounds-a mixtureof (3R)-ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoateand (3R)-ethyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate(1.0 g, 1.009 mmol, 48.6%) which was carried to the next step withoutfurther purification. LC-MS m/z 496.3 (M+H)⁺, 2.03 (ret. time), 510.2(M+H)⁺, 2.06 (ret. time).

(3R)-Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate

To a solution of a mixture of (3R)-ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoateand (3R)-ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate(980 mg, 1.977 mmol) in tetrahydrofuran (THF) (20 mL) at 0° C., TBAF(569 mg, 2.175 mmol) was added. The reaction mixture was stirred at 0°C. for 1 h. The reaction mixture was quenched with saturated. NH₄Clsolution (20 mL), extracted with ethyl acetate (3×50 mL). The organiclayer was washed with water (30 mL) and brine (30 mL), dried over Na₂SO₄and concentrated to obtain the title compounds—a mixture of (3R)-ethyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoateand (3R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(800 mg, 0.965 mmol, 48.8%) which was carried to the next step withoutfurther purification. LC-MS m/z 382.1 (M+H)⁺, 1.56 (ret. time), 396.2(M+H)⁺, 1.60 (ret. time).

(3R)-Ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate

To a solution of a mixture of (3R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoateand (3R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(800 mg, 2.097 mmol) in dichloromethane (DCM) (10 mL) was added thionylchloride (0.184 mL, 2.52 mmol) and one drop DMF. The reaction mixturewas stirred at ambient temperature for 1 h. The solvent was removedunder reduced pressure to obtain the title compounds—a mixture of(3R)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoateand (3R)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate(780 mg, 0.936 mmol, 44.6%) which was carried to the next step withoutfurther purification. LC-MS m/z 400.1 (M+H)+, 2.03 (ret. time), 414.2(M+H)+, 2.07 (ret. time).

(3R)-Ethyl3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate

To a solution of a mixture of (3R)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoateand (3R)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate(780 mg, 1.950 mmol) in acetonitrile (20 mL) was added(R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (346 mg, 1.950mmol) and K₂CO₃ (539 mg, 3.90 mmol). The reaction mixture was stirred at25° C. for 24 h. The solvent was removed under reduced pressure. Theresidue was purified by reverse-phase HPLC (0.05% TFA/H₂O:CH₃CN=5%-95%)to obtain the title compound (3R)-ethyl3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate(300 mg, 0.514 mmol, 26.3% yield). LC-MS m/z 555.3 (M+H)⁺, 1.51 (ret.time).

Ammonium(2S,3R)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanate

To a solution of (3R)-ethyl3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate(300 mg, 0.541 mmol) in methanol (12 mL) was added LiOH (25.9 mg, 1.082mmol). The reaction was heated via microwave reactor for 2 h at 125° C.at high absorption. Then the organic solvent was removed. The residuewas adjusted to pH 6 with 2M HCl (3 mL). After solid was filtered, itwas purified by reverse-phase HPLC (0.05% NH₄HCO₃/H₂O:CH₃CN=5%-95%) toobtain the title compound ammonium(2R,3R)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1Hbenzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid (39 mg, 0.074 mmol, 13.69% yield) (LC-MS m/z 527.3 (M+H)+, 1.67(ret. time)) and title compound ammonium(2S,3R)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid (40 mg, 0.076 mmol, 14.04% yield). LC-MS m/z 527.3 (M+H)⁺, 1.74(ret. time).

Example 102(3R)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid

(R)-Ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of (R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(600 mg, 1.633 mmol) in dichloromethane (DCM) (10 mL) was added thionylchloride (0.143 mL, 1.959 mmol) and one drop DMF. The reaction mixturewas stirred at ambient temperature for 1 h. The solvent was removedunder reduced pressure to obtain the title compound (R)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(560 mg, 1.451 mmol, 89%) which was carried over to next step withoutfurther purification. LC-MS m/z 384.7 (M−H)⁺, 2.03 (ret. time).

(3R)-Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate

To a solution of (R)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(530 mg, 1.373 mmol) in acetonitrile (20 mL) was added2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (219 mg, 1.236 mmol),potassium carbonate (380 mg, 2.75 mmol). The reaction mixture wasstirred at ambient temperature for 16 h. The reaction mixture wasquenched with H₂O (15 mL), extracted with EtOAc (3×50 mL). The organicphase was washed with saturated brine (50 mL), dried over sodium sulfateand concentrated to obtain the title compound (3R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate(480 mg, 0.838 mmol, 61.0% yield) as a brown solid. LCMS m/z 527.3(M+H)⁺, 1.70 (ret. time).

(3R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoate

To a solution of (3R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate(200 mg, 0.380 mmol) in tetrahydrofuran (THF) (5 mL) at −78° C. wasadded lithium diisopropylamide (1.899 mL, 1.899 mmol, 1.0M solution inTHF) The wine red solution was stirred at −78° C. for 45 min andiodomethane (270 mg, 1.899 mmol) was added in one portion and the redwine color turned to light yellow. The reaction mixture was stirred foran additional 45 min at −78° C. The residue was diluted with EtOAc (75mL) and water (25 mL). The aqueous layer was extracted with EtOAc (25mL) and the combined EtOAc layer was washed with saturated NaCl (25 mL),dried over Na₂SO₄ and concentrated. The residue was purified byreverse-phase HPLC (0.05% TFA/H₂O:CH₃CN=5%-95%) to obtain the titlecompound (3R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoate(150 mg, 0.250 mmol, 65.7% yield) as yellow oil. LC-MS m/z 541.3 (M+H)⁺,1.47 (ret. time).

(3R)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid

To a solution of (3R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoate(150 mg, 0.277 mmol) in tetrahydrofuran (THF) (5 mL)/methanol (1 mL) wasadded LiOH (33.2 mg, 1.387 mmol) in water (2.0 mL). The reaction mixturewas stirred at 60° C. for 24 h. Then the organic solvent was removed.The residue was adjusted to pH 5 with HCl (3M, 1.0 mL). Water (10 mL)was added and the reaction mixture was extracted with EtOAc (3×10 m).The organic phase was washed with saturated brine (10 mL), dried oversodium sulfate and concentrated to obtain the title compound(3R)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid (70 mg, 0.131 mmol, 47.3% yield) as a white solid. LC-MS m/z 513.2(M+H)⁺, 1.57 min (ret. time).

Example 103 Ammonium3-(3-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

4-Bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene

To a solution of (5-bromo-2-methylphenyl)methanol (20 g, 99 mmol) inN,N-dimethylformamide (DMF) (120 mL) at 0° C. under nitrogen, sodiumhydride (4.77 g, 119 mmol) was added in two portions. The reactionmixture was stirred at 0° C. for 20 min. Then1-(chloromethyl)-4-methoxybenzene (17.14 g, 109 mmol) was added and thereaction mixture was stirred at 0° C. to 25° C. for 1 h. The reactionmixture was quenched with water (200 mL) and extracted with ethylacetate (3×200 mL). The organic layer was washed with water (2×200 mL)and brine (2×200 mL), dried over Na₂SO₄ and concentrated. The residuewas purified by silica gel chromatography (petroleum ether/ethylacetate=4:1) to give the title compound4-bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene (25 g, 70.0mmol, 70.4% yield) as yellow oil. LC/MS m/z 321.7 (M+H)⁺, 1.90 min (ret.time).

(3-(((4-Methoxybenzyl)oxy)methyl)-4-methylphenyl)(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol

To a solution of4-bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene (642 mg, 1.998mmol) (322 mg, 1.998 mmol) in tetrahydrofuran (THF) (50 mL) was addedbutyllithium (0.879 mL, 2.198 mmol) at −78° C. The reaction mixture wasstirred at −78° C. for 1.5 h under N₂. Then1-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde in THF (10 mL) wasslowly added at −78° C. The reaction mixture was stirred at −78° C. for2 h. Then the reaction mixture was quenched with NH₄Cl saturated aqueoussolution (10 mL) and was extracted with ethyl acetate (3×40 mL), thecombined organic layer was washed with brine (2×10 mL) and dried overanhydrous Na₂SO₄. After filtration and concentration, the crude productwas purified by silica gel chromatography (petroleum ether/ethylacetate=75%) to obtain the title compound(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol(285 mg, 0.678 mmol, 33.9% yield) as colorless oil. LCMS m/z 404.2(M+H)⁺, 1.87 min (ret. time).

Methyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol(285 mg, 0.706 mmol) in dry acetonitrile (10 mL) was slowly added DBU(2.129 μL, 0.014 mmol) and 2,2,2-trichloroacetonitrile (122 mg, 0.848mmol) under N₂ protection. The reaction mixture was stirred at ambienttemperature for 30 min. Then((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (308 mg, 1.766mmol) was added followed by1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (9.93mg, 0.035 mmol) under N₂ protection. The reaction mixture was stirred atambient temperature for 2 h. Water (20 mL) was added to quench thereaction. The mixture was extracted with ethyl acetate (3×10 mL) and theorganic layer was washed with brine, filtered and concentrated to obtainthe title compound methyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(285 mg, 0.678 mmol, 33 9%) which was carried to the next step withoutfurther purification. LC-MS m/z 487.9 (M+H)⁺, 1.83 (ret. time).

Methyl3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of methyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(320 mg, 0.656 mmol) in dichloromethane (DCM) (19 mL) and water (1 mL)was added DDQ (149 mg, 0.656 mmol) at 0° C. The reaction mixture wasstirred at 0° C. for 30 min, then was stirred for an additional 2 h atambient temperature. The reaction mixture was quenched with water (10mL), extracted with ethyl acetate (3×30 mL) and the combined organiclayer was washed with saturated NaHCO₃ (2×10 mL), and brine (2×10 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The crudeproduct was purified by silica gel chromatography (petroleum ether:ethylacetate=75%) to obtain the title compound methyl3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(110 mg, 0.296 mmol, 45.2% yield) as colorless oil. LCMS m/z 367.9(M+H)⁺, 1.54 min (ret. time).

Methyl3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of methyl3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(110 mg, 0.299 mmol) in dichloromethane (DCM) (10.0 mL), SOCl₂ (0.026mL, 0.359 mmol) was added at 0° C. Then the reaction mixture was stirredfor 2 h at 00° C. The reaction mixture was concentrated to obtain thetitle compound methyl3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(110 mg, 0.279 mmol, 93% yield) as colorless oil. LCMS m/z 385.8 (M+H)+,1.75 min (ret. time).

Methyl3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of (R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(50.5 mg, 0.285 mmol) in N,N-dimethylformamide (DMF) (15 mL) at 0° C.under N₂, NaH (12.54 mg, 0.314 mmol) was carefully added. The reactionmixture was stirred at 0° C. for 0.5 h. Then a solution of methyl3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(110 mg, 0.285 mmol) in N,N-dimethylformamide (DMF) (15 mL) was addedand the reaction mixture was stirred at 0° C. to 25° C. for 16 h. Thereaction mixture was quenched with saturated NH₄Cl solution (10 mL) andextracted with EtOAc (3×30 mL). The combined organic layer was washedwith water (2×8 mL) and brine (2×8 mL), dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography(PE:EA=50%) to obtain the title compound methyl3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(50 mg, 0.093 mmol, 32.6% yield) as colorless oil. LC/MS m/z 526.8(M+H)⁺, 1.41 min (ret. time).

Ammonium3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of methyl3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(50 mg, 0.095 mmol) in tetrahydrofuran (THF) (2.0 mL), ethylene glycol(3.0 mL) and water (1.0 mL) was added lithium hydroxide (6.82 mg, 0.285mmol). The reaction mixture was heated in a microwave at 125° C. for 3h. The solvent was removed under vacuum and the residue was dissolvedinto water (2 mL) and acidified to pH 5 by 1 N HCl with ice bathcooling, then it was purified by reverse-phase HPLC (CH₃CN/0.05%NH₃H₂O/H₂O=55%) to obtain the title compound ammonium3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (15 mg, 0.029 mmol, 30.5% yield) as white solid. LC/MS m/z 513.2(M+H)⁺, 1.32 min (ret. time).

Example 1043-(3-((4,5-Dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(70 mg, 0.184 mmol) in dichloromethane (DCM) (2 mL) was added thionylchloride (0.027 mL, 0.367 mmol). The mixture was stirred at ambienttemperature for 40 min. The reaction mixture was concentrated and wasredissolved in acetonitrile (2 mL),2,3,4,5-tetrahydro-1H-benzo[c]azepine (36.7 mg, 0.249 mmol) and DIEA(0.095 mL, 0.543 mmol) were added. The resulting reaction mixture washeated in a Biotage microwave at high absorption for 1 h at 120° C. Thereaction mixture was concentrated and the residue redissolved in MeOH (2mL). 2 M LiOH (0.551 mL, 1.101 mmol) was added and the reaction mixturewas heated in a Biotage microwave at high absorption for 3 h at 120° C.It was acidified with 6N HCl and 0.5 mL DMSO was added. It wasconcentrated and purified with preparative HPLC to give the titlecompound (53.1 mg, 0.107 mmol, 58.3% yield) as solid. LC-MS m/z 497.6(M+H)⁺, 0.79 min (ret. time).

Example 105 Ammonium3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((4,4-dimethyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoate

Ethyl 3-(2-cyanophenyl)-2,2-dimethylpropanoate

To a solution of ethyl isobutyrate (1.185 g, 10.20 mmol) intetrahydrofuran (THF) (20 mL) at −78° C. was added LDA (7.65 mL, 15.30mmol). It was stirred for 45 min afterwhich a solution of2-(bromomethyl)benzonitrile (2 g, 10.20 mmol) in tetrahydrofuran (THF)(10 mL) was added slowly and stirred for 1 h at −78° C. It was warmed toambient temperature for 3 h. The reaction mixture was quenched withsaturated NH₄Cl solution and extracted with DCM (2×30 mL). The combinedorganic layer was washed with brine solution (50 mL). The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated. The cruderesidue was purified by silica gel chromatography to give the titlecompound (1.6 g, 6.92 mmol, 67.8% yield). LC-MS m/z 232.23 (M+H)⁺, 3.72min (ret. time).

3-(2-(Aminomethyl)phenyl)-2,2-dimethylpropan-1-ol

To a solution of ethyl 3-(2-cyanophenyl)-2,2-dimethylpropanoate (1.6 g,6.92 mmol) in tetrahydrofuran (THF) (20 mL) at −78° C. LAH (20.75 mL,20.75 mmol) was added. It was stirred for 30 min at −78° C. and thenallowed to warm to 25° C. for 1 h. The reaction mixture was quenchedwith saturated Na₂SO₄ solution, the solid was filtered and washed withethyl acetate (40 mL). The organic layer was separated from the filtrateand the aqueous layer was extracted with ethyl acetate (2×30 mL). Thecombined organic layer washed with brine solution (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The crude residue waspurified by silica gel chromatography to give the title compound (900mg, 4.48 mmol, 64.7% yield). LC-MS m/z 194.00 (M+H)⁺, 2.19 min (ret.time).

tert-Butyl 2-(3-hydroxy-2,2-dimethylpropyl)benzylcarbamate

To a solution of 3-(2-(aminomethyl)phenyl)-2,2-dimethylpropan-1-ol (500mg, 2.59 mmol) in dichloromethane (DCM) (10 mL) was added Boc₂O (0.601mL, 2.59 mmol) and the reaction stirred for 16 h at ambient temperature.The reaction mixture was diluted with water and extracted with DCM (3×20mL). The combined organic layer dried over anhydrous Na₂SO₄, filteredand concentrated. The crude residue was purified by silica gelchromatography to give the title compound (400 mg, 1.362 mmol, 52.6%yield). LC-MS m/z 294.23 (M+H)⁺, 2.29 min (ret. time).

3-(2-(((tert-Butoxycarbonyl)amino)methyl)phenyl)-2,2-dimethylpropylmethanesulfonate

To a solution of tert-butyl2-(3-hydroxy-2,2-dimethylpropyl)benzylcarbamate (400 mg, 1.363 mmol) indichloromethane (DCM) (10 mL) was added TEA (0.475 mL, 3.41 mmol) andthen cooled to 0° C. Mesyl chloride (0.212 mL, 2.73 mmol) was added andthe reaction stirred at ambient temperature for 2 h. The reactionmixture was diluted with water and extracted with DCM (3×20 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude residue was purified by silica gelchromatography to give the title compound (400 mg, 0.996 mmol, 73.1%yield). LC-MS m/z 372.44(M+H)⁺, 2.45 min (ret. time).

4,4-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine

To a solution of3-(2-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,2-dimethylpropylmethanesulfonate (400 mg, 1.077 mmol) in isopropanol (10 mL) was addedCs₂CO₃ (1052 mg, 3.23 mmol) and copper(I) iodide (20.51 mg, 0.108 mmol).The reaction mixture was heated in a microwave for 3 h at 90° C. Thereaction mixture was filtered through celite and washed with ethylacetate (20 mL). The filtrate was concentrated and purified by silicagel chromatography to give the title compound (90 mg, 0.353 mmol, 32.7%yield) LC-MS m/z 176.13(M+H)⁺, 1.27 min (ret. time).

Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((4,4-dimethyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoate

To a solution of ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(150 mg, 0.389 mmol) in acetonitrile (3 mL) was added4,4-dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine (90 mg, 0.513 mmol)and DIPEA (0.170 mL, 0.972 mmol). The reaction mixture was heated inmicrowave for 30 min at 65° C. The reaction mixture was quenched withsaturated NH₄Cl solution and extracted with DCM (2×30 mL). The combinedorganic layer was washed with brine solution (50 mL). The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated. The cruderesidue was purified by silica gel chromatography to give the titlecompound (120 mg, 0.192 mmol, 83.82% yield) LC-MS m/z 525.0 (M+H)⁺,5.736 min (ret. time).

Ammonium3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((4,4-dimethyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoate

To a solution of ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((4,4-dimethyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoate(120 mg, 0.229 mmol) in ethanol (5 mL) was added NaOH (0.286 mL, 0.572mmol). It was stirred for 2 h at ambient temperature. The reactionmixture was concentrated and acidified with 1N HCl solution (6 mL) to pH2. The resulting suspension was filtered, dried, and purified withpreparative HPLC to give the title compound (40 mg, 0.080 mmol, 35.0%yield) LC-MS m/z 497.40 (M+H)⁺, 1.75 min (ret. time).

Example 1063-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((4-ethyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoicacid

Ethyl 2-(2-cyanobenzyl)butanoate

To a solution of ethyl butyrate (0.681 mL, 5.10 mmol) in tetrahydrofuran(THF) (10 mL) at −78° C., was added lithium diisopropylamide (2M in THF)(3.83 mL, 7.65 mmol) slowly. After 30 min, a solution of2-(bromomethyl)benzonitrile (1 g, 5.10 mmol) in THF (2 mL) was addedslowly. It was stirred at −78° C. for 3 h. The reaction mixture wasquenched with ammonium chloride solution (50 mL) and extracted withEtOAc (2×20 mL). The combined organic layer was washed with brinesolution (20 mL) and dried over Na₂SO₄, filtered and concentrated. Thecrude residue was purified by silica gel chromatography to give thetitle compound (600 mg, 2.360 mmol, 46.3% yield) as a colorless liquid.LCMS m/z: 232.17 (M+H)⁺, 3.716 min (ret.time)

2-(2-(Aminomethyl)benzyl)butan-1-ol

To a solution of ethyl 2-(2-cyanobenzyl)butanoate (600 mg, 2.59 mmol) intetrahydrofuran (THF) (10 mL) at ambient temperature was added LAH (7.78mL, 7.78 mmol) slowly. The reaction mixture was stirred for 3 h. Thereaction mixture was quenched with ammonium chloride solution andextracted with EtOAc (2×50 mL). The combined organic layer was driedover Na₂SO₄, filtered and concentrated. The crude residue was purifiedby silica gel chromatography to give the title compound (400 mg, 2.069mmol, 80% yield). LCMS m/z: 194 (M+H)⁺, 3.036 min (ret.time)

(2-(2-(Chloromethyl)butyl)phenyl)methanamine

To a solution of 2-(2-(aminomethyl)benzyl)butan-1-ol (400 mg, 2.069mmol) in 1,2-dichloroethane (DCE) (10 mL) at 5° C. was added sulfurousdichloride (0.302 mL, 4.14 mmol) slowly. The reaction mixture wasallowed to stir at ambient temperature for 15 h. It was concentrated andquenched with saturated sodium bicarbonate and extracted with DCM (2×25mL). The combined organic layer was washed with brine solution (20 mL),dried over Na₂SO₄, filtered and concentrated. The crude residue waspurified by silica gel chromatography to give the title compound (300mg, 1.417 mmol, 68.5% yield). LCMS m/z: 212 (M+H)⁺, 1.94 min (ret.time)

4-Ethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine

To a solution of (2-(2-(chloromethyl)butyl)phenyl)methanamine (300 mg,1.417 mmol) in acetonitrile (2 mL) was added DIPEA (1.237 mL, 7.08mmol). The reaction mixture was stirred at ambient temperature for 16 h.It was concentrated and extracted with DCM (2×50 mL). The organic layerwas dried over Na₂SO₄, filtered, and concentrated. The crude residue waspurified by silica gel chromatography to give the title compound (180mg, 1.027 mmol, 72.5% yield). LCMS m/z:176.22 (M+H)⁺, 1.33 min(ret.time)

Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((4-ethyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoate

To a solution of 4-ethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine (150 mg,0.856 mmol) in acetonitrile (5 mL) was added DIPEA (0.149 mL, 0.856mmol) and ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(132 mg, 0.342 mmol). The reaction mixture was heated at 80° C. for 1 h.The reaction mixture was quenched with water and extracted with ethylacetate (3×20 mL). The combined organic layer washed with brine solution(20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. Thecrude residue was purified by silica gel chromatography to give thetitle compound (100 mg, 0.191 mmol, 22.27% yield) as gum. LCMS m/z:524.32(M+H)⁺, 2.017 min (ret.time)

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((4-ethyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoicacid

To a solution of ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((4-ethyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoate(100 mg, 0.191 mmol) in ethanol (2 mL) at ambient temperature was added2 M NaOH in water (0.191 mL, 0.381 mmol). The reaction mixture wasstirred at ambient temperature for 15 h. The reaction mixture wasconcentrated and acidified with 1N HCl to pH 1. It was extracted withDCM (2×10 mL). The combined organic layer was washed with brine solution(20 mL), dried over Na₂SO₄, filtered and concentrated. The crude residuewas purified by silica gel chromatography to give the title compound (42mg, 0.084 mmol, 44.1% yield) as a pale yellow solid. LCMS: m/z: 497.36(M+H)⁺, 1.800 min (ret.time)

The compounds in Table 13 were prepared by a method similar to the onedescribed for the preparation of3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((4-ethyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-4-methylphenyl)propanoicacid. As is appreciated by those skilled in the art, these analogousexamples may involve variations in general reaction conditions.

TABLE 13 LCMS Retention Ex # Structure Name [M + H]⁺ Time (min) Example107

3-(1,4-dimethyl-1H- benzo[d][1,2,3]triazol-5- yl)-3-(3-((4-ethyl-8-fluoro-4,5-dihydro-1H- benzo[c]azepin-2(3H)- yl)methyl)-4-methylphenyl)propanoic acid 515.43 1.852

Example 1083-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,8-trimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid, formic acid salt

4-chloro-6-methylnicotinoyl chloride

4-hydroxy-6-methylnicotinic acid (5 g, 32.7 mmol) in phosphoryltrichloride (30.4 mL, 327 mmol) was refluxed at 106° C. for 3 hours. Thesolution was cooled and excess phosphoryl trichloride was removed invacuo with a rotary evaporator. The crude product was azeotropicallydried with toluene (3×25 mL) and dried under high vacuum to give thetitle compound (6 g, 31.6 mmol, 97% yield), which was taken to the nextstep without purification. LC/MS: m/z 189.8, 191.8 (M+H)⁺, 0.89 min(ret. time).

4-chloro-N-(2-hydroxy-2-methylpropyl)-6-methylnicotinamide

Sodium hydroxide (52.3 mL, 105 mmol) was added dropwise to a solution of4-chloro-6-methylnicotinoyl chloride (6.21 g, 32.7 mmol) and1-amino-2-methylpropan-2-ol (4.37 g, 49.1 mmol) in dichloromethane (DCM)(54.5 mL) at 0° C. and allowed to warm to ambient temperature whilestirring vigorously. The reaction was complete after 3 hours. The DCMand aqueous NaOH layers were separated and the aqueous NaOH fractionextracted with DCM (3×50 mL). The combined organic fractions were dried(sodium sulfate) and the solvent removed in vacuo. The product waspurified by flash chromatography (combiflash 20-100% Hexanes/EtOAc:EtOH(3:1)) to give the title compound (1.9 g, 7.83 mmol, 23.94% yield) over2 steps. LC/MS: m/z 242.9, 244.9 (M+H)⁺, 0.5 min (ret. time).1-(((4-chloro-6-methypyridin-3-)methyl)amino-2-methylpropan-2-ol

Borane dimethyl sulfide (6.18 mL, 12.36 mmol) was added to a solution of4-chloro-N-(2-hydroxy-2-methylpropyl)-6-methylnicotinamide (500 mg,2.060 mmol) in tetrahydrofuran (THF) (41.203 mL) and heated to reflux.The reaction was complete after 5 hours. The reaction was then cooled to0° C. and methanol (MeOH) (20 mL) was added dropwise. The solvent wasthen removed under vacuum to give the title compound (471 mg, 2.059mmol, 100% yield) which was taken to the next step without furtherpurification. LC/MS: m/z 228.9 (M+H)⁺, 0.49 min (ret. time).

Tert-butyl2,2,8-trimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepine-4(5H)-carboxylate

1-(((4-chloro-6-methylpyridin-3-yl)methyl)amino)-2-methylpropan-2-ol(0.471 g, 2.06 mmol) and potassium tert-butoxide (0.462 g, 4.12 mmol) indimethyl sulfoxide (DMSO) (13.73 mL) were heated to 80° C. in a biotagemicrowave reactor (high intensity) for 1 hour. Solid sodium bicarbonatewas added and the suspension was filtered. The filtrate was concentratedand the crude material redissolved in tetrahydrofuran (THF) (6.87 mL).The solution was cooled to 0° C. and triethylamine (0.417 g, 4.12 mmol)followed by di-tert-butyl dicarbonate (1.349 g, 6.18 mmol) was added.The solution was allowed to warm to ambient temperature and the reactionwas complete after 12 hours. The solvent was removed in vacuo and theproduct purified by flash chromatography on a Combiflash instrument(0-100% EtOAc/Hexanes) to give the title compound (20 mg, 0.068 mmol,3.32% yield). LC/MS: m/z 293.0 (M+H)⁺, 0.70 min (ret. time).

2,2,8-trimethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepinehydrochloride

tert-Butyl2,2,8-trimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepine-4(5H)-carboxylate(20 mg, 0.068 mmol) in hydrogen chloride (4 M in dioxane) (1026 μl, 4.10mmol) was stirred at ambient temperature for 3 hours. The solvent wasremoved under a stream of nitrogen at 50° C. to give the title compound(15.65 mg, 0.068 mmol, 100% yield). LC/MS: m/z 193.0 (M+H)⁺, 0.28 min(ret. time).

Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,8-trimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoate

Ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(18.98 mg, 0.049 mmol),2,2,8-trimethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepinehydrochloride (15 mg, 0.066 mmol), and N-ethyl-N-isopropylpropan-2-amine(17.18 μl, 0.098 mmol) in acetonitrile (293 μl) were heated in a Biotagemicrowave reactor at high absorption for 1 h at 120° C. The solvent wasremoved to give the title compound (35.5 mg, 0.066 mmol, 100% yield).LC/MS: m/z 542.3 (M+H)⁺, 0.94 min (ret. time).

3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,8-trimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid, formic acid salt

Sodium hydroxide (0.270 mL, 0.539 mmol) was added to a solution of ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,8-trimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoate(27 mg, 0.049 mmol) in methanol (0.408 mL) at ambient temperature andstirred for 18 hours. DMSO (3 mL) was added and the methanol was removedin vacuo. The solution was acidified with 1N HCl and the aqueousfraction removed in vacuo. The crude product was purified byreverse-phase HPLC (with 0.1% formic acid) to give the title compound(19 mg, 0.034 mmol, 69.3% yield). LC/MS: m/z 514.4 (M+H)⁺, 0.75 min(ret. time).

Example 109(S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, formic acid salt

(S)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

Thionyl chloride (0.397 mL, 5.44 mmol) was added to a solution of(S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(1 g, 2.72 mmol) in dichloromethane (DCM) (5.44 mL) at ambienttemperature and stirred for 1 h. Solvent was concentrated in vacuo togive the title compound (1.050 g, 2.72 mmol, 100% yield) LC/MS: m/z386.1 (M+H)⁺, 1.16 min (ret. time).

(S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate

(S)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(150 mg, 0.389 mmol),2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride (166mg, 0.777 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.204 mL, 1.166mmol) in acetonitrile (2.718 mL) were heated in a Biotage microwavereactor at high power for 60 minutes at 120° C. The solvent was removedto give the title compound (204.7 mg, 0.389 mmol, 100% yield). LC/MS:m/z 527.4 (M+H)⁺, 0.97 min (ret. time).

(S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, formic acid salt

Sodium hydroxide (2.140 mL, 4.28 mmol) was added to a solution of(S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate(205 mg, 0.389 mmol) in methanol (3.242 mL) at ambient temperature andstirred for 18 hours. The solution was acidified with 1 N HCl andconcentrated. The solution was acidified with 1N HCl and the aqueousfraction removed in vacuo. The crude product was purified byreverse-phase HPLC (with 0.1% formic acid) to give the title compound(140.2 mg, 0.257 mmol, 66.2% yield). LC/MS: m/z 499.5 (M+H)⁺, 0.74 min(ret. time).

Example 110(R)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, formic acid salt

(R)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

Thionyl chloride (0.397 mL, 5.44 mmol) was added to a solution of(R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(1 g, 2.72 mmol) in dichloromethane (DCM) (5.44 mL) at ambienttemperature and stirred for 30 min. Solvent was concentrated in vacuo togive the title compound (1.050 g, 2.72 mmol, 100% yield. LC/MS: m/z386.1 (M+H)⁺, 1.15 min (ret. time).

(R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate

(R)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(150 mg, 0.389 mmol),2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride (166mg, 0.777 mmol), N-ethyl-N-isopropylpropan-2-amine (0.204 mL, 1.166mmol) in acetonitrile (2.72 mL) were heated in a Biotage microwavereactor at high power for 1 hour at 120° C. The solvent was removed togive the title compound (204.7 mg, 0.389 mmol, 100% yield). LC/MS: m/z527.4 (M+H)⁺, 0.95 min (ret. time).

(R)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, formic acid salt

Sodium hydroxide (2.140 mL, 4.28 mmol) was added to a solution of(R)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate(205 mg, 0.389 mmol) in methanol (3.242 mL) at ambient temperature andstirred for 18 hours. The solution was acidified with 1N HCl andconcentrated. The crude product was purified by reverse-phase HPLC (with0.1% formic acid) to give the title compound (153.89 mg, 0.283 mmol,72.6% yield). LC/MS: m/z 499.5 (M+H)⁺, 0.76 min (ret. time).

Example 1113-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1-ethyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, formic acid salt

Ethyl 2-((2-nitrobenzyl)amino)acetate

To 1-(bromomethyl)-2-nitrobenzene (20 g, 93 mmol) inN,N-dimethylformamide (DMF) (200 mL) was added ethyl 2-aminoacetate,hydrochloride (19.38 g, 139 mmol) and DIPEA (48.5 mL, 278 mmol) slowlyunder nitrogen at 25° C. The reaction mixture was stirred at 25° C. for6 h afterwhich 500 mL of water was added and the mixture extracted withethyl acetate (3×200 mL). The combined organic layer was dried overMgSO₄ and concentrated. The crude product was purified by silica gelchromatography (hexane:ethyl acetate=10:1) to give the title compoundethyl 2-((2-nitrobenzyl)amino)acetate (16 g, 67.2 mmol, 72.5% yield)which was carried to the next step without further purification. LC-MSm/z 239.1 (M+H)⁺, 1.20 min (ret. time).

Ethyl 2-((tert-butoxycarbonyl)(2-nitrobenzyl)amino)acetate

To ethyl 2-((2-nitrobenzyl)amino)acetate (16 g, 67.2 mmol) indichloromethane (DCM) (200 mL) was added Boc₂O (23.39 mL, 101 mmol),DMAP (0.410 g, 3.36 mmol) and TEA (18.72 mL, 134 mmol) slowly undernitrogen at 25° C. The reaction mixture was stirred at 25° C. for 16 h.The solvent was evaporated and the crude product was purified by silicagel chromatography (hexane:ethyl acetate=10:1) to give the titlecompound ethyl 2-((tert-butoxycarbonyl)(2-nitrobenzyl)amino)acetate (16g, 46.8 mmol, 69.7% yield) which was carried to the next step withoutfurther purification. LC-MS m/z 361.1 (M+Na)⁺, 2.06 min (ret. time).

Ethyl 2-((2-aminobenzyl)(tert-butoxycarbonyl)amino)acetate

A solution of ethyl 2-((tert-butoxycarbonyl)(2-nitrobenzyl)amino)acetate(16 g, 47.3 mmol) in methanol (500 mL) was degassed for 10 min withargon, Pd/C (5 g, 4.70 mmol) was added. Then it was stirred for 22 hunder H₂ balloon. The reaction mixture was filtered through celite andthe filtrate was concentrated to give the title compound ethyl2-((2-aminobenzyl)(tert-butoxycarbonyl)amino)acetate (14 g, 45.4 mmol,96% yield) which was carried to the next step without furtherpurification. LC-MS m/z 309.1 (M+H)⁺, 1.87 min (ret. time).

Tert-butyl 2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate

To ethyl 2-((2-aminobenzyl)(tert-butoxycarbonyl)amino)acetate (14 g,45.4 mmol) in toluene (700 mL) was added HOBt (5.56 g, 36.3 mmol) slowlyunder nitrogen at ambient temperature. The reaction mixture was stirredat 110° C. for 16 h. The solvent was evaporated and the crude productwas purified by silica gel chromatography (hexane:ethyl acetate=4:1) togive the title compound tert-butyl2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate (8.6 g,31.8 mmol, 70.1% yield) which was carried to the next step withoutfurther purification. LC-MS m/z 207.1 (M+H-t-tutyl)⁺ 1.74 min (ret.time).

tert-Butyl-ethyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate

To tert-butyl2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate (8.6 g,32.8 mmol) in N,N-dimethylformamide (DMF) (200 mL) was added NaH (2.229g, 55.7 mmol) slowly under nitrogen at 25° C. After it was stirred at25° C. for 30 min, iodoethane (7.67 g, 49.2 mmol) solution in 1 ml ofDMF was added. The reaction mixture was stirred at ambient temperaturefor 2 h, then 50 mL of water was added and the mixture extracted withethyl acetate (3×100 mL). The combined organic layer was dried overMgSO₄, and concentrated to give the title compound tert-butyl1-ethyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate (9g, 31.0 mmol, 95% yield) which was carried to the next step withoutfurther purification. LC-MS m/z 309.1 (M+23)⁺, 1.91 min (ret. time).

1-Ethyl-4,5-dihydro-1H-benzo[e][1,4]diazepin-2(3H)-one

To tert-butyl1-ethyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate (9g, 31.0 mmol) in dichloromethane (DCM) (150 mL) was added TFA (50 ml,649 mmol) slowly under nitrogen at 25° C. The reaction mixture wasstirred at 25° C. for 16 h. The solvent was evaporated. 100 mL of 20% ofNa₂CO₃ was added and extracted with ethyl acetate (3×100 mL). Thecombined organic layer was dried over MgSO₄ and concentrated to give thetitle compound 1-ethyl-4,5-dihydro-1H-benzo[e][1,4]diazepin-2(3H)-one(4.2 g, 22.08 mmol, 71.2% yield) which was carried to the next stepwithout further purification. LC-MS m/z 191.1 (M+H)⁺, 1.06 min (ret.time).

1-Ethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine

To 1-ethyl-4,5-dihydro-1H-benzo[e][1,4]diazepin-2(3H)-one (4.2 g, 22.08mmol) in tetrahydrofuran (THF) (50 mL) was added LiAlH₄ (1.006 g, 26.5mmol) slowly under nitrogen at 0° C. The reaction was stirred at 0° C.for 30 min and stirred at 60° C. for 6 h. It was cooled to 0° C., water(1 mL) and 1 mL of 10% NaOH were added, followed by an additional 3 mLof water. The mixture was filtered and the filtrate was concentrated.The crude product was purified by silica gel chromatography(hexane:ethyl acetate:triethylamine=1:4:0.05) to give the title compound1-ethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (1.6 g, 8.17 mmol,37.0% yield) as oil. LC-MS: m/z 177.2 (M+H)⁺, 1.51 min (ret. time).

Methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

Thionyl chloride (0.727 mL, 9.96 mmol) was added to a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(1.9 g, 4.98 mmol) in dichloromethane (DCM) (9.96 mL) at ambienttemperature and stirred for 1 hour. The solution was concentrated invacuo to give the title compound (1.99 g, 4.98 mmol, 100% yield). LC/MS:m/z 400.1 (M+H)⁺, 1.16 min (ret. time).

Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1-ethyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

Methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(60 mg, 0.150 mmol),1-ethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (34.4 mg, 0.195mmol), and N-ethyl-N-isopropylpropan-2-amine (0.081 mL, 0.466 mmol) inacetonitrile (0.670 mL) were heated in a Biotage microwave reactor athigh power for 1 hour at 120° C. The solvent was removed in vacuo togive the title compound (81 mg, 0.150 mmol, 100% yield). LC/MS: m/z540.3 (M+H)⁺, 1.01 min (ret. time).

3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1-ethyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, formic acid salt

Lithium hydroxide (2.66 mg, 0.111 mmol) was a added to a solution ofmethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1-ethyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate(60 mg, 0.111 mmol) in water (285 μl) and methanol (570 μl) and heatedin a Biotage microwave reactor at high power at 130° C. for 2 hours. Thecrude product was purified by reverse-phase HPLC (with 0.1% formic acid)to give a yellow solid (40 mg, 0.070 mmol, 62.9% yield). LC/MS: m/z526.5 (M+H)⁺, 0.79 min (ret. time).

Example 112(2R)-4-(5-(1-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-(1H-tetrazol-5-yl)ethyl)-2-methylbenzyl)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine,formic acid salt

(E)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylonitrile

To a solution of 5-bromo-1,4-dimethyl-1H-benzo[d][1,2,3]triazole (1.00g, 4.42 mmol) in N,N-dimethylformamide (DMF) (11 mL) in a 20 mLmicrowave reaction vessel was added acrylonitrile (1.747 mL, 26.5 mmol),tri-o-tolylphosphine (0.404 g, 1.327 mmol), and DIEA (3.09 mL, 17.69mmol). The solution was flushed with nitrogen for 3 min and thenpalladium(II) acetate (0.149 g, 0.664 mmol) was added. The reaction washeated via microwave at 150° C. for 2 h. Additional palladium(II)acetate (0.149 g, 0.664 mmol) was added and the reaction was heated viamicrowave at 150° C. for 1.5 h. The reaction was filtered through Celiteand washed with EtOAc. The filtrate was washed with water (3×). Thecombined organics were washed with brine, dried with MgSO₄, and solventswere concentrated. The residue was purified by flash chromatographyeluting with 0-10% EtOAc/DCM and repurified by flash chromatographyeluting with 0-40% EtOAc/Hexane to provide the title compound as amixture of cis and trans isomers. (0.583 g, 66% yield) LC-MS m/z 199(M+H)⁺, 0.67 min (ret. time).

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanenitrile

To a solution of(E)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylonitrile (0.583g, 2.94 mmol) and (3-(hydroxymethyl)-4-methylphenyl)boronic acid (0.586g, 3.53 mmol) in 1,4-dioxane (25 mL) and water (15 mL) was addedtriethylamine (0.615 mL, 4.41 mmol) and,chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.145 g, 0.294 mmol). Thereaction was heated at 95° C. for 3.5 h. The reaction was cooled and thesolvents were concentrated. The residue was diluted with water andextracted with EtOAc. The combined organics were washed with water (2×)and the aqueous layers were backextracted with EtOAc. The combinedorganics were washed with water, brine, and dried with MgSO₄, and thesolvent was concentrated. The residue was purified by flashchromatography eluting with 0-30% EtOAc/hexane to provide the titlecompound. (0.62 g, 65% yield) LC-MS m/z 320.0 (M+H)⁺, 0.74 min (ret.time).

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanenitrile

To a solution of3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanenitrile(0.275 g, 0.858 mmol) in dichloromethane (DCM) (8 mL) was added thionylchloride (0.125 mL, 1.717 mmol) and stirred at ambient temperature for 1h. The reaction was evaporated and the residue was suspended inacetonitrile (8.00 mL). DIEA (0.450 mL, 2.58 mmol) and(R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine, hydrochloride(0.202 g, 0.944 mmol) was added to the suspension and the reaction wasstirred at ambient temperature for 3 h. The solvents were concentratedand the residue was purified by flash chromatography, eluting with 0-40%EtOAc/Hexane to provide the title compound. (0.087 g, 18% yield) LC-MSm/z 480 (M+H)⁺, 0.88 min (ret. time).

(2R)-4-(5-(1-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-(1H-tetrazol-5-yl)ethyl)-2-methylbenzyl)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine,formic acid salt

A mixture of3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanenitrile(0.087 g, 0.181 mmol), TMS-N₃ (0.072 mL, 0.544 mmol) and TBAF (0.253 g,0.907 mmol) were heated in a 20 mL vial at 85° C. for 1 h. Afterwhich,additional TMS-N₃ (0.072 mL, 0.544 mmol was added and heated at at 85°C. for 18.5 h. Additional TMS-N₃ (0.072 mL, 0.544 mmol) was then addedand continued heating for 18 h. The residue was purified by reversephase preparative HPLC under neutral conditions and then acidicconditions to provide the title compound. (0.025 g, 24% yield) LC-MS m/z523 (M+H)⁺, 0.71 min (ret. time).

Example 1133-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid

(2-Bromopyridin-3-yl)methanamine

To a solution of 2-bromo-3-(bromomethyl)pyridine, hydrochloride (1.81 g,6.30 mmol) in ethanol (4 mL) was added ammonium hydroxide (50 mL, 1284mmol) and stirred at 50° C. for 30 min. The reaction was diluted withwater and aqueous layer was extracted with EtOAc (12×, 600 mL total).The combined organics were washed with brine and dried with MgSO₄. Thesolvent was concentrated and the residue residue was purified by flashchromatography eluting with 0-5% MeOH/DCM to provide the title compound.(0.750 g, 63% yield) LC-MS m/z 187 (M+H)⁺, 0.10 min (ret. time).

(R)-1-(((2-bromopyridin-3-yl)methyl)amino)butan-2-ol

A solution of (2-bromopyridin-3-yl)methanamine (1.27 g, 6.79 mmol) and(R)-2-ethyloxirane (0.490 g, 6.79 mmol) in ethanol (10 mL) in a 20 mLmicrowave reaction vessel was heated via microwave at 150° C. for 2 h.The solvent was concentrated and the residue was purified by flashchromatography eluting with 0-50-90% (3:1 EtOAc:ethanol)/hexane toprovide the title compound. (0.934 g, 53% yield) LC-MS m/z 542 (M+H)+,0.83 min (ret. time).

(R)-2-ethyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine

To a solution of (R)-1-(((2-bromopyridin-3-yl)methyl)amino)butan-2-ol(1.365 g, 5.27 mmol) in N,N-Dimethylformamide (DMF) (20 mL) was addedpotassium tert-butoxide (1.773 g, 15.80 mmol) and heated to 80° C. for1.5 h. The reaction was cooled, filtered and washed with DMF. Thesolvent was concentrated under vacuum and the residue was purified byflash chromatography eluting with 0-5% MeOH/DCM to provide the titlecompound. (0.890 g, 95% yield) LC-MS m/z 179 (M+H)+, 0.23 min (ret.time).

Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(0.075 g, 0.197 mmol) in dichloromethane (DCM) (2 mL) was added thionylchloride (0.042 mL, 0.575 mmol) and stirred at ambient temperature for 2h. The solvents were concentrated. The residue,(R)-2-ethyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.035 g,0.197 mmol) and DIEA (0.137 mL, 0.786 mmol) were dissolved inacetonitrile (4 mL) in a 10 mL microwave reaction vessel and heated to120° C. for 30 min. The solvent was concentrated and the residue residuewas purified by flash chromatography eluting with 0-60% (3:1EtOAc:Ethanol)/Hexane to provide the title compound. (0.075 g, 64%yield) LC-MS m/z 542 (M+H)⁺, 0.83 min (ret. time).

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate(75 mg, 0.138 mmol) dissolved in tetrahydrofuran (THF) (2 mL), water (1mL). and methanol (0.5 mL) in a 10 mL microwave reaction vessel wasadded lithium hydroxide (16.58 mg, 0.692 mmol) and heated via microwaveat 125° C. for 8 h. The solvent was concentrated and the residue wasacidified with formic acid. The residue was purified by reverse phasepreparative HPLC under acidic conditions to provide the title compound.(0.037 g, 50% yield) LC-MS m/z 528 (M+H)⁺, 0.72 min (ret. time).

Example 1143-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, Lithium salt

Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-formyl-4-methylphenyl)-2,2-dimethylpropanoate

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(75 mg, 0.197 mmol) in dichloromethane (DCM) (5 mL) was addedDess-Martin periodinane (100 mg, 0.236 mmol) at 0° C. and was stirredfor 2 h. The reaction mixture was purified via by flash chromatographyeluting 0-100% EtOAc/Hexanes to provide the title compound (70 mg, 75%yield) as a white foam. LC-MS m/z 380 (M+H)+, 1.01 min (ret. time).

Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-formyl-4-methylphenyl)-2,2-dimethylpropanoate(70 mg, 0.184 mmol) in dichloromethane (DCM) (3 mL) was added(R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride (59.1mg, 0.277 mmol) under an argon atmosphere. The two reagents were stirredtogether for 1.5 h and then sodium triacetoxyborohydride (78 mg, 0.369mmol) was added as the solid in one portion. The reaction was stirredfor 30 min and was quenched with water (5 mL), diluted with CH₂Cl₂ (15mL) and the layers separated. The organic layer was dried with sodiumsulfate and concentrated. The residue was purified by flashchromatography eluting 0-100% EtOAc/Hexanes to provide the titlecompound. (0.040 g, 36% yield) LC-MS m/z 541 (M+H)+, 0.90 min (ret.time).

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, Lithium salt

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate(80 mg, 0.148 mmol) in water (2.000 mL) and methanol (2.000 mL) wasadded lithium hydroxide (3.54 mg, 0.148 mmol) in a 5 mL microwave vial.The reaction was stirred at ambient temperature for 10 min to make ahomogenous solution and then heated on the microwave for 90 min at 125°C. The reaction was purified by reverse phase preparative HPLC underneutral conditions to provide the title compound. (0.028 g, 36% yield)LC-MS m/z 527 (M+H)+, 0.86 min (ret. time).

Example 1153-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(4-fluoro-2-methylphenyl)-2,2-dimethylpropanoicacid, formic acid salt

To a solution of methyl3-(4-fluoro-2-methylphenyl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(110 mg, 0.319 mmol) in dichloromethane (DCM) (5 mL) was added thionylchloride (0.047 mL, 0.639 mmol). The resulting mixture was stirred atroom temperature for 1 h. The solvent was then removed by evaporationand the residue was redissolved in N,N-dimethylformamide (DMF) (5 mL).To that solution was added DIEA (0.223 mL, 1.278 mmol) and(R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride (102mg, 0.479 mmol). The reaction mixture was heated to 75° C. and stirredfor 18 h. To the reaction mixture was added LiOH (38.2 mg, 1.597 mmol)and Water (5.00 mL) and heated to 60° C. for 18 h. The reaction has notprogressed so the sample was heated in the Biotage microwave reactor at120° C. for 3 h. The reaction mixture was acidified with formic acid andconcentrated. The sample was purified by reverse phase preparative HPLCunder acidic conditions to obtain mainly methyl3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(4-fluoro-2-methylphenyl)-2,2-dimethylpropanoate.The ester was redissolved in water (5.00 mL) and N,N-dimethylformamide(DMF) (5 mL) and reexposed to LiOH (38.2 mg, 1.595 mmol) under the samemicrowave conditions as previously. The residue was concentrated andredissolved in minimal DMSO and purified by reverse phase preparativeHPLC under acidic conditions to yield3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(4-fluoro-2-methylphenyl)-2,2-dimethylpropanoicacid, formic acid salt (45 mg, 0.083 mmol, 26.0% yield) as a auburn oil.LC-MS m/z 490 (M+H)+, 0.99 min (ret. time).

Example 1163-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, formic acid salt

Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate

To a solution of ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)phenyl)propanoate(100 mg, 0.272 mmol) in DCM (2 mL) was added thionyl chloride (65 mg,0.544 mmol) and stirred for 1 h. The solvent was concentrated andresidue was redissolved in acetonitrile (4 mL) and(R)-2-ethyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (58 mg, 0.327mmol) and DIEA (141 mg, 1.089 mmol) were added and heated via microwaveat 120° C. The solvent was concentrated and the residue was purified viaby flash chromatography eluting 0-50-70% (3:1 EtOAc:Ethanol)/Hexane toprovide the title compound (15 mg, 10% yield). LC-MS m/z 528 (M+H)+,0.82 min (ret. time).

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, formic acid salt

To a solution of ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate(15 mg, 0.028 mmol) in THF (2 mL)/water (1 mL) was added lithiumhydroxide (3 mg, 0.125 mmol) and stirred at ambient temperature for 18h. The reaction was then heated at 50° C. for 2 h. Additional lithiumhydroxide (3 mg, 0.125 mmol) was added and the reaction was heated for 6h and then for 18 h at ambient temperature. The reaction was thenacidified with formic acid and the solvents were concentrated. Theresidue was purified by reverse phase preparative HPLC under acidicconditions to provide the title compound. (0.006 g, 42% yield) LC-MS m/z500 (M+H)+, 0.69 min (ret. time).

Example 1173-(2,4-Difluorophenyl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, formic acid salt

(E)-Methyl 3-(2,4-difluorophenyl)acrylate

Trimethyl phosphonoacetate (1.425 mL, 8.80 mmol) in tetrahydrofuran(THF) (30 mL) was added KOtBu (0.987 g, 8.80 mmol) and stirred at roomtemperature for 10 min before adding 2,4-difluorobenzaldehyde (0.875 mL,8 mmol) in tetrahydrofuran (THF) (5 mL). The resulting reaction mixturewas stirred at room temperature for 160 min. To the reaction mixture wasadded more trimethyl phosphonoacetate (0.648 mL, 4.00 mmol) then KOtBu(0.449 g, 4.00 mmol). The resulting reaction mixture was stirred at roomtemperature for 30 min. The reaction mixture was added H₂O (20 mL),extracted with EtOAc (3×30 mL). The combined organic layer was washedwith brine (20 mL), dried over MgSO₄, filtered and concentrated to givethe title compound (1.5710 g, 7.93 mmol, 99% yield). LCMS: m/z: 199.1(M-17)⁺, 0.94 min (ret.time)

Methyl3-(2,4-difluorophenyl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

(E)-methyl 3-(2,4-difluorophenyl)acrylate (396 mg, 2 mmol) in1,4-dioxane (10 mL) and water (3 ml) was treated with(3-(hydroxymethyl)-4-methylphenyl)boronic acid (664 mg, 4.00 mmol),triethylamine (1.115 mL, 8.00 mmol) and [RhCl(cod)]₂ (49.3 mg, 0.100mmol). The resulting reaction mixture was stirred at 90° C. for 19 h.The reaction mixture was extracted with EtOAc (3×15 mL). The combinedorganic layer was dried over MgSO₄, filtered and concentrated. The crudeproduct was purified with silica gel chromatography to give the titlecompound (522.3 mg, 1.631 mmol, 82% yield). LCMS: m/z: 303.1 (M-17)⁺,0.98 min (ret.time)

3-(2,4-Difluorophenyl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, formic acid salt

To a solution of methyl3-(2,4-difluorophenyl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(110 mg, 0.223 mmol) in dichloromethane (DCM) (5 mL) was added thionylchloride (0.033 mL, 0.446 mmol). The resulting mixture was stirred atambient temperature for 1 h. The solvent was then removed by evaporationand the residue was redissolved in N,N-dimethylformamide (DMF) (5 mL).To that solution was added DIEA (0.156 mL, 0.893 mmol) and(R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride (71.6mg, 0.335 mmol). The reaction mixture was heated to 75° C. and stirredfor 18 h. Afterwards, LiOH (26.7 mg, 1.116 mmol) and water (5.00 mL) wasadded to the reaction mixture and heated to 60° C. for 18 h. Thereaction mixture was acidified with formic acid and concentrated. Theresidue was purified by reverse phase preparative HPLC under acidicconditions to provide the title compound. (34.7 mg, 31.9% yield) LC-MSm/z 466 (M+H)+, 0.96 min (ret. time) as a brown oil.

Example 1185-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoicacid ISOMER 1

Pent-4-ynal

DMSO (5.58 g, 71.4 mmol) was added dropwise to a solution of oxalylchloride (4.53 g, 35.7 mmol) in dichloromethane (DCM) (80 mL) at −78° C.The mixture was stirred at −78° C. for 15 min, pent-4-yn-1-ol (2.0 g,23.8 mmol) in DCM (20 mL) was added dropwise to the reaction mixture andthe mixture was stirred 15 min. Et₃N (10.84 g, 107.1 mmol) was added andthe reaction mixture was stirred an additional 15 min, then the reactionmixture was warmed to 0° C. and quenched with water. The aqueous layerwas extracted with DCM. The combined organic phase was washed withwater, brine and dried over Na₂SO₄. The organic layer was concentrated,giving 0.6 g (31%) of the title compound. ¹H NMR (400 MHz, CHLOROFORM-d)b ppm 2.54 (td, J=7.03, 2.51 Hz, 2H); 2.68-2.76 (m, 2H); 4.72 (s, 1H);9.83 (s, 1H).

(E)-Ethyl hept-2-en-6-ynoate

NaH (1.056 g, 26.4 mmol) was added in small portions to a solution ofethyl 2-(diethoxyphosphoryl)acetate (3.03 mL, 14.4 mmol) in DCM (15 mL).The mixture was stirred at 23° C. for 5 min, crude pent-4-ynal (0.985 g,−1 mL, 12 mmol) in DCM (10 mL) was added slowly, and the mixture wasstirred at 23° C. for 30 min. NH₄Cl (saturated aqueous) was added andthe solution was extracted with DCM. The crude product was purified bysilica gel chromatography to give the title compound (1.32 g, 72%).LC-MS m/z 153.0 (M+H)⁺, 0.82 (ret. time).

(E)-ethyl 5-(1-ethyl-1H-1,2,3-triazol-4-yl)pent-2-enoate

NaN₃ (0.085 g, 1.31 mmol), CuI (0.25 mg, 1.31 umol) and iodoethane(0.090 mL, 1.31 mmol) was added to a solution of (E)-ethylhept-2-en-6-ynoate (0.2 g, 1.31 mmol) in water (5 mL), the mixture wasstirred at 70° C. for 14 h. The mixture was concentrated and waspurified by silica gel chromatography to give the title compound (100mg, 34%). LC-MS m/z 224.1 (M+H)⁺, 0.65 (ret. time).

Ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)pentanoate

(3-(Hydroxymethyl)-4-methylphenyl)boronic acid (0.11 g, 0.67 mmol), Et₃N(0.094 mL, 0.67 mmol) and [RhCl(cod)]₂ (11 mg, 0.022 mmol) were added toa solution of (E)-ethyl 5-(1-ethyl-1H-1,2,3-triazol-4-yl)pent-2-enoate(0.1 g, 0.45 mmol) in 1,4-Dioxane (1 mL) and Water (0.5 mL). Thereaction was heated in a microwave at 140° C. (high absorption) for 4 h.The mixture was concentrated and purified by silica gel chromatographyto give the title compound (64 mg, 41%) Ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)pentanoateand 50 mg recovered (E)-ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)pent-2-enoate. LC-MS m/z 346.2 (M+H)⁺,0.81 (ret. time).

Ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate

To a solution of ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)pentanoate(4.2 g, 7.78 mmol) in N,N-Dimethylformamide (DMF) (30 mL) at 4° C. wasadded imidazole (2.483 g, 36.5 mmol) followed bytert-butyldimethylchlorosilane (3.21 g, 21.30 mmol). The reaction wasallowed to stir for 2 h while warming from 4° C. to 23° C. slowly. Thereaction was poured over ice water and extracted with DCM. Combinedorganic layers were washed with water before being concentrated. Cruderesidue was purified by silica gel chromatography to give the titlecompound (3.07 g, 6.68 mmol, 86% yield). LCMS m/z 460.2 [M+H]⁺, 1.45 min(ret. time).

Ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoatemajor disastereomer

Diisopropylamine (0.341 mL, 2.393 mmol) in tetrahydrofuran (THF) (18 mL)was cooled to −78° C. and then 2M n-butyllithium (1.03 mL, 2.060 mmol)was added and the mixture was stirred at −78° C. for 45 min. Ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate(1.0 g, 2.175 mmol) in tetrahydrofuran (THF) (18 mL) was added dropwise(T<-70° C.) and the resulting mix was kept at −70° C. for 45 min andthen iodomethane (2.72 mL, 43.5 mmol) was added. The reaction was warmedslowly to 23° C. and stirred 30 min. The reaction was diluted with water(150 mL) and ethyl acetate (EtOAc) (3×75 mL). The combined EtOAc waswashed with saturated aq NaCl (50 mL), dried (Na₂SO₄) and concentrated.The crude product was dissolved in THF (16 mL) and 1 M TBAF in THF (4mL, 4.00 mmol) was added and stirred 16 h. The reaction was diluted withEtOAc (200 mL) and washed with water (75 mL) and saturated aqueous NaCl(50 mL), dried (Na₂SO₄) and concentrated to afford a yellow oil as adiastereomeric mixture of monomethyl alcohols and recovered startingmaterials. The crude product was dissolved in acetonitrile (4 mL),filtered and was purified by reverse-phase HPLC (with 0.1% TFAcondition) to give the title compound as predominantly the majordiastereomer ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoateas an oil. This was resubmitted to reverse phase chromatography toafford pure major diastereomer (96 mg). LC-MS m/z=360.3 (M+H)⁺0.87 (ret.time).

Enantiomer A (first to elute from SFC), Ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate

Combined samples of the major diastereomer from the above separation and4 methylation reactions run under similar conditions and diastereomerseparations of the same substrate were combined to afford 550 mg of themajor diastereomer ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate.These were separated into the pure enantiomers by Chiral SFC (ChiralpakIC, 20×150, 5 u and co-solvent 25% IPA, total flow rate: 50 g/min, backpressure: 100 bar). The first enantiomer to elute was collected anddried. The dried compounds were transferred to pre-weighted 20 mL vialwith IPA, and dried under N₂ stream at 45° C. to afford: Enantiomer A(first to elute from SFC), Ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate(141 mg). LC-MS m/z=360.2 (M+H⁺) 0.86 (ret. time). sfc λ=220 (nm), 2.61(ret. time).

Enantiomer B (second to elute from SFC), Ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate

Enantiomer B (second to elute from SFC), ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate(136 mg). LC-MS m/z=360.2 0.86 (ret. time). SFC A=220 (nm), 3.04(ret.time)

Ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoateenantiomer A configuration)

To a solution of Ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate(141 mg, 0.392 mmol) Enantiomer A (first to elute from sfc) indichloromethane (DCM) (4 mL) was added thionyl chloride (0.100 mL, 1.373mmol). The resulting mixture was stirred at 23 C for 1 h. DCM wasremoved in vacuo and N,N-dimethylformamide (DMF) (4.00 mL) was added.(R)-2-Ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride (126mg, 0.588 mmol) and DIEA (0.274 mL, 1.569 mmol) were added and themixture was heated to 75° C. for 1.5 h the reaction was cooled to 23° C.The reaction was partly concentrated in vacuo and the residual solutionwas diluted with EtOAc (75 mL) and ˜0.5M aq NaOH (25 mL) shaken andseparated. The aqueous phase was extracted again with EtOAc (25 mL) andthe combined EtOAc was washed with water (25 mL) and satd aq NaCl (25mL), dried (Na₂SO₄) filtered and concentrated. The crude product wasdissolved in acetonitrile (˜9.5 mL), filtered and then purified byreverse-phase HPLC (with 0.1% TFA condition) to give the title compoundto afford ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoate(225 mg, 0.434 mmol, 111% yield) as a light green oil. LC-MS m/z=519.3(M+H)⁺, 0.95 (ret. time).

5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoicacid ISOMER 1

Ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoate(225 mg, 0.434 mmol) was dissolved in tetrahydrofuran (THF) (4. mL) andlithium hydroxide (208 mg, 8.68 mmol) dissolved in Water (4.00 mL) wasadded and then methanol (2 mL) was added. The resulting mixture washeated in a microwave at high setting at 100° C. for 30 min. Cooled to23° C., a drop was diluted with water and acetonitrile to afford a clearsolution. Icms indicated the desired product but only ˜2/3 conversionbased on uv214. Run for 90 min at 110° C. Reaction 100% converted.Volatile was partially removed in vacuo and the remaining basic aqueoussolution was diluted with water (˜10 mL) and washed with EtOAc (10 mL)and hexane (10 mL). The aqueous phase was combined with TFA (˜0.5 mL),diluted to a total volume of 15 mL, filtered and then purified byreverse-phase HPLC (with 0.1% TFA condition) to give the title compound5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoicacid (186 mg, 0.379 mmol, 87% yield). The diastereoisomers wereseparated by chiral SFC (Chiralpak AD, 20×250, 5 u 20% co-solvent: 20%IPA, total flow rate: 50 g/min, back pressure: 100 bar) to afford thefirst isomer to elute5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoicacid ISOMER 1 (97 mg). LC-MS m/z=491.4 (MH⁺), 0.82 (ret. time). SFCA=220 (nm), 3.99 (ret. time). Area %=100%

Example 1195-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoicacid ISOMER 2

The second isomer to elute from the above sfc separation was5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoicacid ISOMER 2 (10 mg). Icms m/z=491.4 (MH⁺), 0.82 (ret. time). sfc λ=220(nm), 5.58 (ret. time).

Example 1205-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoicacid ISOMER 3

Ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoateenantiomer B configuration)

To a solution of Ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate(136 mg, 0.378 mmol) enantiomer B (second to elute from sfc) prepared asdescribed in ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate,in dichloromethane (DCM) (4 mL) was added thionyl chloride (0.097 mL,1.324 mmol). The resulting mixture was stirred at 23° C. for 2.5 h andthe reaction was concentrated and the residue was dissolved inN,N-dimethylformamide (DMF) (4.00 mL) to which was added DIEA (0.264 mL,1.513 mmol) and (R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepinehydrochloride (121 mg, 0.568 mmol) and the mixture was heated to 75° C.for 1 h. The reaction was partly concentrated in vacuo and the residualsolution was diluted with EtOAc (75 mL) and 0.5M aq NaOH (25 mL) shakenand separated. The aq phase was extracted again with EtOAc (25 mL) andthe combined EtOAc was washed with water (25 mL) and saturated aqueousNaCl (25 mL), dried (Na₂SO₄) filtered. The crude product was purified byflash chromatography on a silica gel chromatography to give the titlecompound (158 mg, 0.305 mmol, 81% yield). LC-MS m/z=519.4 (M+H+), 0.94(ret. time).

5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoicacid ISOMER 3

Ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoate(158 mg, 0.305 mmol) was dissolved in tetrahydrofuran (THF) (4.0 mL) andLiOH (146 mg, 6.09 mmol) dissolved in water (4.0 mL) and methanol (2.0mL) and the resulting mixture was heated in a microwave at high settingat 100° C. for 30 min. Cooled, a drop was diluted with water andacetonitrile to afford a clear solution. Icms indicated the desiredproduct but only 2/3 conversion based on uv-214. Re-run for 1 h at 110C. Volatile was partially removed in vacuo and the remaining basic aqsolution was diluted with water (10 mL) and washed with EtOAc (10 mL)and hexane (10 mL). The aqueous phase was combined with TFA (˜0.5 mL),diluted to a total volume of 15 mL, filtered through a 0.45 mm acrodisc,and injected in 4 portions onto Gilson HPLC (Sunfire C18, 5 m 30×250mm), eluting at 30 mL/min with a linear gradient running from 10%CH3CN/H2O (0.1% TFA) to 90% CH3CN/H2O (0.1% TFA) over 10 min to afford5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoicacid (63 mg, 0.128 mmol, 42.2% yield) The isomers were separated bychiral SFC (Chiralpak AD, 20×250, 5 u 20% co-solvent: 20% IPA, totalflow rate: 50 g/min, Back pressure: 100 bar) to afford the first isomerto elute5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoicacid ISOMER 3 (28 mg). LC-MS m/z=491.4 (M+H+), 0.82 (ret. time). sfcA=220 (nm), 5.17 (ret. time)

Example 121(S)-3-(3-((2-(Cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate,sodium salt

Methyl 2-cycloheptylacetate

To a solution of 2-cycloheptylacetic acid (4.76 g, 30.5 mmol) inmethanol (50 mL) was added sulfuric acid (2.99 g, 30.5 mmol) slowly.Then it was stirred at 70° C. for 16 h. After it was cooled to ambienttemperature, the reaction mixture was added to 50 mL of water andextracted with ethyl acetate (3×50 mL), washed with brine, concentratedto obtain the title compound methyl 2-cycloheptylacetate (5.18 g, 28.3mmol, 92.9% yield). LCMS m/z 171.2 (M+H)⁺, 1.82 min (Ret. time)

2-Cycloheptylethanol

To a solution of methyl 2-cycloheptylacetate (4.33 g, 25.4 mmol) intetrahydrofuran (THF) (20 mL) was added lithium aluminum hydride (1.931g, 50.9 mmol) slowly under nitrogen at 0° C. and stirred for 1 hour.Then the reaction mixture was stirred at 25° C. for 16 hours. Then 30 mLof HCl (3 M) was added, extracted with EtOAc (3×30 mL), washed withbrine, dried over MgSO₄ and concentrated to obtain the title compound2-cycloheptylethanol (3.28 g, 20.75 mmol, 82% yield) as a white oil. ¹HNMR (400 MHz, DMSO-d₆) □=4.26 (t, J=4.9 Hz, 1H), 3.41 (q, J=5.9 Hz, 2H),1.73-1.29 (m, 13H), 1.22-1.08 (m, 2H)

2-Cycloheptylacetaldehyde

To a solution of 2-cycloheptylethanol (3.28 g, 23.06 mmol) indichloromethane (DCM) (50 mL) was added PCC (7.46 g, 34.65 mmol) andsilica gel (15 g). The reaction mixture was stirred at 25° C. for 16 h.Then it was filtered through a pad of celite. The filtrate wasconcentrated under vacuum. The crude product was purified by silica gelchromatography (EtOAC:Hexane=1:5) to obtain the title compound2-cycloheptylacetaldehyde (1.30 g, 8.81 mmol, 38.2% yield) as a yellowoil. ¹H NMR (400 MHz, CDCl₃) δ=9.74 (s, 1H), 2.32-1.28 (m, 15H).

2-(Cycloheptylmethyl)-1H-imidazole

To a solution of 2-cycloheptylacetaldehyde (1.2 g, 8.56 mmol) inmethanol (36 mL) and water (36 mL) was added oxaldehyde (0.993 g, 17.12mmol) and ammonia hydrate (2.189 g, 62.5 mmol). The reaction mixture wasstirred at 0° C. for 2 h, then it was stirred at ambient temperature for18 h. The solid was filtered and dried under vacuum to obtain the titlecompound 2-(cycloheptylmethyl)-1H-imidazole (680 mg, 3.43 mmol, 40.1%yield) as a white solid. LCMS m/z 179.2 (M+H)⁺, 1.22 min (ret. time)

(S)-3-(3-((2-(Cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate,sodium salt

To a solution of 2-(cycloheptylmethyl)-1H-imidazole (145 mg, 0.813 mmol)in N,N-dimethylformamide (DMF) (5 mL) was added NaH (62.5 mg, 1.563mmol). The mixture was stirred at 25° C. for 40 min. A solution of(S)-methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(250 mg, 0.625 mmol) in N,N-dimethylformamide (DMF) (3 mL) was added.The mixture was stirred at ambient temperature for 20 h. It was quenchedwith saturated NH₄Cl, extracted with ethyl acetate twice. The combinedorganic layer was concentrated to give the crude product. It waspurified by silica gel chromatography. Desired fractions wereconcentrated and re-dissolved in methanol (5.00 mL). LiOH (1.875 mL,3.75 mmol) was added and the mixture was heated in a Biotage microwaveat high absorption for 6 h at 120° C. It was acidified with 1N HCl topH˜1. 5 mL DMSO was added and the solvent was concentrated. The crudeproduct was purified by reverse-phase HPLC (with 0.1% TFA condition) togive the title compound as TFA salt. It was re-dissolved in ethylacetate (10 mL), extracted with saturated NaHCO₃. The aqueous layer wasextracted with ethyl acetate. The combined organic layer was dried oversodium sulfate, filtered and then concentrated to give title compound(142 mg, 0.258 mmol, 41.3% yield) as solid. LC-MS m/z 528.3 (M+H)⁺, 0.87min (ret. time)

The compounds in Table 14 were prepared by a method similar to the onedescribed for the preparation of(S)-3-(3-((2-(cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate,sodium salt. As is appreciated by those skilled in the art, theseanalogous examples may involve variations in general reactionconditions.

TABLE 14 LCMS Retention Ex # Structure Name [M + H]⁺ Time (min) Example122

(S)-3-(1,4-Dimethyl- 1H- benzo[d][1,2,3]triazol- 5-yl)-3-(3-((2-((4-ethylpiperidin-1- yl)methyl)-1H- imidazol-1-yl)methyl)-4-methylphenyl)-2,2- dimethylpropanoate, Sodium salt 543.5 0.76 Example123

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-2,2-dimethyl-3-(4-methyl-3-((2- (piperidin-1- ylmethyl)-1H- imidazol-1-yl)methyl)phenyl) propanoate, Sodium salt 515.4 0.67 Example 124

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-2,2-dimethyl-3-(4-methyl-3-((2- (pyrrolidin-1- ylmethyl)-1H- imidazol-1-yl)methyl)phenyl) propanoate, Sodium salt 515.5 0.81 Example 125

(R)-3-(3-((2- (Cycloheptylmethyl)- 1H-imidazol-1- yl)methyl)-4-methylphenyl)-3-(1,4- dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-2,2-dimethylpropanoate, Sodium salt 528.3 0.85 Example 126

(S)-3-(3-((2-(Azepan-1- ylmethyl)-1H- imidazol-1-yl)methyl)-4-methylphenyl)-3- (1,4-dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-2,2-dimethylpropanoate, Sodium salt 529.3 0.77

Example 1273-(3-((2-(Cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

2-Cyclohexylacetaldehyde

To a solution of 2-cyclohexylethanol (1.0 g, 7.80 mmol) indichloromethane (DCM) (50 mL), was added PCC (2.52 g, 11.70 mmol). Thereaction mixture was stirred at ambient temperature for 2 hrs afterwhich it was diluted with diethyl ether (500 mL) and was stirred atambient temperature for 1 hr and filtered through a pad of celite andsilica gel (1:1). The filtrate was concentrated to give the titlecompound 2-cyclohexylacetaldehyde (570 mg, 4.52 mmol, 57.9% yield). ¹HNMR (400 MHz, CHCL3-d) □ ppm 1.15 (m, 2H), 1.28 (m, 3H), 1.73 (m, 5H),1.91 (m, 1H), 2.30 (d, J=2.0 Hz, 2H), 9.75 (s, 1H).

2-(Cyclohexylmethyl)-1H-imidazole

To a solution of oxalaldehyde (3.22 g, 22.19 mmol) in water (30 mL) wasadded 2-cyclohexylacetaldehyde (2.8 g, 22.19 mmol). After the resultantsolution was cooled to 10° C. in an ice/water bath, ammonium hydroxide(0.4 ml, 2.88 mmol) was added and the reaction stirred for 18 hrs. Theresulting precipitate was filtered and dried under the vacuum to affordthe title compound 2-(cyclohexylmethyl)-1H-imidazole (520 mg, 3.17 mmol,14.27% yield). LC-MS m/z 165.2 (M+H)⁺, 1.16 (ret. time).

3-(3-((2-(Cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

To a solution of 2-(cyclohexylmethyl)-1H-imidazole (200 mg, 1.218 mmol)in N,N-dimethylformamide (DMF) (30 mL) was added NaH (73.1 mg, 1.827mmol) at 00° C. The reaction mixture was stirred at 0° C. for 1 hr afterwhich ethyl3-(3-(bromomethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(210 mg, 0.487 mmol) was added to the reaction mixture. The reactionmixture was stirred at 00° C. for 4 hrs. Water (20 mL) was added and thereaction extracted with ethyl acetate (3×30 mL). The combined organiclayer was washed with water and brine, dried with MgSO₄ and concentratedto give a crude product that was purified by preparative HPLC to affordthe title compound3-(3-((2-(cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (75 mg, 0.151 mmol, 12.42% yield). LC-MS m/z 486.4 (M+H)⁺, 1.43(ret. time).

Example 1283-(3-((1-(Cyclohexylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

1-(Cyclohexylmethyl)-1H-1,2,3-triazole

To a solution of 1H-1,2,3-triazole (2.5 g, 36.2 mmol) inN,N-dimethylformamide (DMF) (30 mL), (bromomethyl)cyclohexane (7.69 g,43.4 mmol) was added Cs₂C₀₃ (23.59 g, 72.4 mmol) and sodium iodide (5.43g, 36.2 mmol). The reaction mixture was stirred at 100° C. for 2 hrsafter which the reaction mixture was cooled to ambient temperature andfiltered. The filtrate was concentrated and was purified by silica gelchromatography (petroleum ether:ethyl acetate=2:1) to afford the titlecompound 1-(cyclohexylmethyl)-1H-1,2,3-triazole (1.0 g, 6.05 mmol,16.72% yield). LC-MS m/z 166.1 (M+H)⁺, 1.52 (ret. time).

Ethyl3-(3-((1-(cyclohexylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of 1-(cyclohexylmethyl)-1H-1,2,3-triazole (110 mg, 0.666mmol) in tetrahydrofuran (THF) (20 mL) was added nBuLi (0.250 mL, 0.599mmol) dropwise at −70° C. The reaction mixture was stirred at thattemperature for 30 min after which ethyl3-(3-(bromomethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(100 mg, 0.232 mmol) in THF (2 ml) was added at −70° C. The reactionmixture was stirred for another 1 hr. After the reaction mixture waswarmed to ambient temperature, 20 mL of water was added and the mixtureextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed with water and brine, dried with MgSO₄ and concentrated to give acrude product that was purified by preparative HPLC to afford the titlecompound ethyl3-(3-((1-(cyclohexylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(87 mg, 0.169 mmol, 25.4% yield). LC-MS m/z 515.2 (M+H)⁺, 2.72 (ret.time).

3-(3-((1-(Cyclohexylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

To a solution of ethyl3-(3-((1-(cyclohexylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(79 mg, 0.153 mmol) in tetrahydrofuran (THF) (10 mL) and water (4 mL)was added LiOH (160 mg, 6.68 mmol). The reaction mixture was stirred at40° C. for 20 h. The reaction mixture was acidified with HCl (1 N) andthe mixture extracted with ethyl acetate (3×20 mL). The combined organiclayers were dried with MgSO₄ and concentrated to provide a crude productthat was purified by preparative HPLC to afford the title compound3-(3-((1-(cyclohexylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (32 mg, 0.066 mmol, 42.8% yield). LC-MS m/z 487.3 (M+H)⁺, 1.62(ret. time).

Example 1293-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)propanoicacid

2-((Tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazole

To a solution of oxalaldehyde (340 mg, 2.341 mmol) in water (3.6 mL) wasadded 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (300 mg, 2.341 mmol). Theresulting solution was cooled to 10° C. in an ice/water bath after whichammonium hydroxide (0.4 ml, 2.88 mmol) was added. The reaction mixturewas stirred for 18 h and the resulting precipitate was filtered anddried under vacuum to afford the title compound2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazole (150 mg, 0.902 mmol,38.6% yield). LC-MS m/z 167.2 (M+H)⁺, 0.32 (ret. time).

Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)propanoate

To a solution of 2-((tetrahydro-2-pyran-4-yl)methyl)-1H-imidazole 0.9mg, 0.349 mmol) in N,N-dimethylformamide (DMF) (3.0 mL) was added DIPEA(0.183 mL, 1.046 mmol) and ethyl3-(3-(bromomethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(150 mg, 0.349 mmol). The reaction mixture was stirred at 100° C. for 4hrs after which the reaction mixture was concentrated under reducedpressure and purified by preparative HPLC (50% MeOH/H₂O) to afford thetitle compound ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)propanoate(100 mg, 0.194 mmol, 55.6% yield). LC-MS m/z 516.3 (M+H)⁺, 1.42 (ret.time).

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)propanoicacid

To a solution of ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)propanoate(85 mg, 0.165 mmol) in methanol (5 mL) was added a solution of NaOH(19.78 mg, 0.495 mmol) in H₂O (1 mL). The reaction mixture was stirredat 20° C. for 4 hrs. The reaction mixture was concentrated and theresidue was acidified with 1N HCl to pH=3. The crude product waspurified by preparative HPLC (50% MeOH/H₂O) to afford the title compound3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)propanoicacid (45 mg, 0.090 mmol, 54.3% yield). LC-MS m/z 488.3 (M+H)⁺, 1.18(ret. time).

Example 1303-(3-((2-(Cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)pentanoicacid

(E)-Ethyl hept-2-en-6-ynoate

To a solution of ethyl 2-(diethoxyphosphoryl)acetate (24.03 g, 107 mmol)in tetrahydrofuran (THF) (150 mL) was added sodium hydride (4.68 g, 117mmol)) in small portions. After the reaction mixture was stirred for 5mins, pent-4-ynal (8.0 g, 97 mmol) was added slowly and the mixturestirred at ambient temperature for 30 mins after which NH₄Cl (sat. aq.)was added and the reaction mixture was extracted with DCM. The organiclayer was washed with brine, dried with MgSO₄ and concentrated. Theresidue was purified via silica gel chromatography with PE/EA=50/1 togive the title compound (E)-ethyl hept-2-en-6-ynoate (12 g, 79 mmol, 81%yield). ¹H NMR (400 MHz, CHCl₃-d) δ ppm 1.29 (t, 3H), 2.01 (s, 1H), 2.41(m, 4H), 4.21 (q, 2H), 5.87 (d, 1H), 6.96 (m, 1H).

(E)-Ethyl 5-(1-methyl-1H-1,2,3-triazol-4-yl)pent-2-enoate

A mixture of methyl iodide (4.93 mL, 79 mmol), (E)-ethylhept-2-en-6-ynoate (4.0 g, 26.3 mmol), sodium azide (5.13 g, 79 mmol),DIPEA (4.59 mL, 26.3 mmol) and copper(I) iodide (0.050 g, 0.263 mmol) inwater (10 mL) and THF (20 mL) were stirred at 70° C. for 2 hrs. Thereaction mixture was concentrated and the residue was extracted withethyl acetate (3×50 mL). The combined organic layer was dried with MgSO₄and concentrated. The crude product was purified by preparative HPLC toafford the title compound (E)-ethyl5-(1-methyl-1H-1,2,3-triazol-4-yl)pent-2-enoate (3.0 g, 13.62 mmol,51.8% yield). LC-MS m/z 210.1 (M+H)⁺, 1.35 (ret. time).

Ethyl3-(3-(hydroxymethyl)-4-methylphenyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)pentanoate

To a suspension of (E)-ethyl5-(1-methyl-1H-1,2,3-triazol-4-yl)pent-2-enoate (200 mg, 0.956 mmol),(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(711 mg, 2.87 mmol) and Et₃N (0.799 mL, 5.73 mmol) in a mixture of1,4-dioxane (5 mL) and water (2 mL) at ambient temperature was addedchloro(1,5-cyclooctadiene)rhodium(I) dimer (23.56 mg, 0.048 mmol). Theresulting suspension was heated at 95° C. for 10 hrs. The reactionmixture was diluted with water (30 mL) and the mixture extracted withEtOAc (3×30 mL). The combined organic phases were washed with water,brine, dried over MgSO₄ and concentrated. The crude product was purifiedby silica gel chromatography (petroleum ether:ethyl acetate=2:1) toafford the title compound ethyl3-(3-(hydroxymethyl)-4-methylphenyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)pentanoate(120 mg, 0.362 mmol, 37.9% yield). LC-MS m/z 322.3 (M+H)⁺, 1.13 (ret.time).

Ethyl3-(3-(chloromethyl)-4-methylphenyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)pentanoate

A mixture of ethyl3-(3-(hydroxymethyl)-4-methylphenyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)pentanoate(120 mg, 0.362 mmol) and SOCl₂ (0.032 mL, 0.435 mmol) in dichloromethane(DCM) (2.0 mL) was stirred at ice bath for 2 hrs. The reaction mixturewas concentrated to afford crude the title compound ethyl3-(3-(chloromethyl)-4-methylphenyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)pentanoate(140 mg, 0.400 mmol, 111% yield). LC-MS m/z 350.1 (M+H)⁺, 1.26 (ret.time).

Ethyl3-(3-((2-(cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)pentanoate

To a solution of 2-(cyclohexylmethyl)-1H-imidazole (46.9 mg, 0.286 mmol)in N,N-dimethylformamide (DMF) (3.0 mL) was added DIPEA (0.150 mL, 0.857mmol) and ethyl3-(3-(chloromethyl)-4-methylphenyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)pentanoate(100 mg, 0.286 mmol). After the reaction mixture was stirred at 100° C.for 4 hrs, it was concentrated. The crude product was purified bypreparative HPLC (50% MeOH/H₂O) to afford the title compound ethyl3-(3-((2-(cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)pentanoate(110 mg, 0.23 mmol, 81% yield). LC-MS m/z 478.4 (M+H)⁺, 1.48 (ret.time).

3-(3-((2-(Cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)pentanoicacid

To a solution of ethyl3-(3-((2-(cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)pentanoate(110 mg, 0.230 mmol) in methanol (5 mL) was added a solution of NaOH(27.6 mg, 0.691 mmol) in H₂O (1 mL). The reaction mixture was stirred at20° C. for 4 hrs then concentrated. The residue was acidified with 1NHCl to pH=3 and the crude product was purified by preparative HPLC (50%MeOH/H₂O) to give the title compound3-(3-((2-(cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)pentanoicacid (70 mg, 0.148 mmol, 64.2% yield). LC-MS m/z 450.3 (M+H)⁺, 1.44(ret. time).

Example 1313-(3-((2-(Cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

Methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(400 mg, 1.049 mmol) in dichloromethane (DCM) (10.0 mL), SOCl₂ (0.092mL, 1.258 mmol) was added. The reaction mixture was stirred at 0° C. for2 h. Then the reaction mixture was concentrated to obtain the titlecompound methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(400 mg, 0.960 mmol, 92% yield) as a colorless oil which was carriedover to the next step without further purification. LCMS m/z 400.1(M+H)⁺, 1.77 min (ret. time)

Methyl3-(3-((2-(cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To a solution of 2-(cycloheptylmethyl)-1H-imidazole (134 mg, 0.750 mmol)in N,N-dimethylformamide (DMF) (10 mL) was added sodium hydride (45.0mg, 1.875 mmol) and stirred for 30 min at 0° C. Methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(150 mg, 0.375 mmol) in DMF(10 mL) was added to the reaction mixtureslowly and stirred for 1 h at 0° C. Then saturated NH₄Cl solution wasadded and the mixture extracted with EtOAc (3×20 mL). The organic layerwas washed with water (2×20 mL) and brine (2×20 mL), dried over Na₂SO₄and concentrated to obtain the title compound methyl3-(3-((2-(cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(190 mg, 0.333 mmol, 89% yield) as a yellow oil. LCMS m/z 542.3 (M+H)⁺,1.36 min (ret. time)

3-(3-((2-(Cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

To a solution of methyl3-(3-((2-(cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(200 mg, 0.369 mmol) in tetrahydrofuran (THF) (3 mL) was added lithiumhydroxide (88 mg, 3.69 mmol) in water (1 mL) and ethylene glycol (2 mL).The reaction was heated in a microwave at 125° C. for 4 h. Then theorganic solvent was removed. The residue was purified by reverse-phaseHPLC (0.05% NH₄HCO₃/H₂O:CH₃CN=5-95%) to obtain the title compound3-(3-((2-(cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid (12 mg, 0.022 mmol, 5.97% yield) as a white solid. LCMS m/z 528.3(M+H)⁺, 1.62 min (ret. time)

Example 1323-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylcyclohexyl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)propanoicacid

Ethyl 2-(4-ethylcyclohexylidene)acetate

A solution of triethyl phosphonoacetate (9.52 mL, 47.5 mmol) intetrahydrofuran (THF) (100 mL) at 0° C. was treated with NaH (1.521 g,38.0 mmol) under nitrogen. The reaction mixture was stirred at 0° C. for1 h. Then a solution of 4-ethylcyclohexanone (4.0 g, 31.7 mmol) intetrahydrofuran (THF) (100 mL) was added to the reaction mixture. It wasstirred at ambient temperature for 4 h. The reaction mixture was dilutedwith ethyl acetate (100 mL) and washed with water (2×100 mL). Theorganic layer was dried over sodium sulfate and concentrated. The crudeproduct was purified by silica gel chromatography (petroleum ether/ethylacetate=10:1) to give the title compound ethyl2-(4-ethylcyclohexylidene)acetate (3.8 g, 19.36 mmol, 61.1% yield) asoil. ¹H NMR (400 MHz, CDCl₃) δ=5.61 (s, 1H), 4.16-4.11 (q, 2H), 3.76 (m,1H), 2.29-2.13 (m, 2H), 1.93-1.89 (m, 3H), 1.41 (m, 1H), 1.28-1.23 (m,5H), 1.07 (m, 2H), 0.89 (t, 3H).

Ethyl 2-(4-ethylcyclohexyl)acetate

A mixture of ethyl 2-(4-ethylcyclohexylidene)acetate (3.3 g, 16.81 mmol)and Pd/C (10%) (1.789 g, 16.81 mmol) in ethanol (10 mL) was hydrogenatedwith H₂ balloon for 8 h. The reaction mixture was filtered throughcelite and concentrated to obtain the title compound ethyl2-(4-ethylcyclohexyl)acetate (2.5 g, 12.61 mmol, 75.0% yield) as an oil.¹H NMR (400 MHz, CDCl₃) δ=4.13 (q, 2H), 2.17-2.16 (m, 2H), 1.75-1.73 (m,4H), 1.5 (m, 1H), 1.26-1.20 (m, 6H), 0.93-0.84 (m, 7H).

2-(4-Ethylcyclohexyl)ethanol

To a solution of ethyl 2-(4-ethylcyclohexyl)acetate (2200 mg, 11.09mmol) was dissolved in tetrahydrofuran (THF) (8.0 mL) at 0° C. was addedLiAlH₄ (1053 mg, 27.7 mmol). The reaction mixture was stirred at 0° C.for 8 h. Then 1 M hydrochloric acid was added to the reaction mixtureand extracted with ethyl acetate (3×50 mL). The organic layer was washedwith saturated sodium chloride solution, dried over magnesium sulfateand concentrated to obtain the title compound2-(4-ethylcyclohexyl)ethanol (1500 mg, 9.60 mmol, 87% yield) as an oil.¹H NMR (400 MHz, CDCl₃) δ=3.69 (q, 2H), 1.75 (m, 3H), 1.48-1.40 (m, 4H),1.32-1.18 (m, 4H), 0.91-0.85 (m, 6H).

2-(4-Ethylcyclohexyl)acetaldehyde

To a solution of 2-(4-ethylcyclohexyl)ethanol (1500 mg, 9.60 mmol) indichloromethane (DCM) (15.0 mL), PCC (3104 mg, 14.40 mmol) was added.The reaction mixture was stirred at 10° C. for 2 h. The reaction mixturewas diluted with diethyl ether (500 mL) and stirred at ambienttemperature for 1 h. Then it was filtered through a pad of celite andsilica gel (1:1). The filtrate was carefully concentrated to dryness togive the title compound 2-(4-ethylcyclohexyl)acetaldehyde (750 mg, 4.86mmol, 50.7% yield). ¹H NMR (400 MHz, CDCl₃) δ=9.75 (s, 1H), 2.30-2.28(m, 2H), 1.77-1.74 (m, 4H), 1.5 (m, 1H), 1.22-1.29 (m, 4H), 1.0-1.85 (m,6H).

2-((4-Ethylcyclohexyl)methyl)-1H-imidazole

To a solution of 2-(4-ethylcyclohexyl)acetaldehyde (750 mg, 4.86 mmol)in water (2 ml), oxaldehyde (282 mg, 4.86 mmol) and ammonium hydroxide(3.0 mL, 21.57 mmol) were added. The reaction mixture was stirred at 10°C. for 2 h. The solid was filtered and dried to obtain the titlecompound 2-((4-ethylcyclohexyl)methyl)-1H-imidazole (100 mg, 0.520 mmol,10.70% yield). LCMS m/z 193.2 (M+H)⁺, 1.23 min (ret. time).

Ethyl3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylcyclohexyl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)propanoate

To a solution of 2-((4-ethylcyclohexyl)methyl)-1H-imidazole (50 mg,0.260 mmol) in N,N-dimethylformamide (DMF) (3.0 mL), DIPEA (0.045 mL,0.260 mmol) was added. Then ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(100 mg, 0.260 mmol) was added to the reaction. The reaction mixture wasstirred at 100° C. for 4 h. Then it was purified by reverse-phase HPLCto give the title compound ethyl 3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylcyclohexyl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)propanoate(85 mg, 0.157 mmol, 60.3% yield) as a solid. LC-MS m/z 542.2 (M+H)⁺,1.48 min (ret. time)

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylcyclohexyl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)propanoicacid

To a solution of ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylcyclohexyl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)propanoate(85 mg, 0.157 mmol) in methanol (5 mL), NaOH (18.83 mg, 0.471 mmol) inH₂O (1 mL) was added. The reaction mixture was stirred at 20° C. for 4h. The solvent was evaporated and the residue was neutralized with 1NHCl to pH 3. The product was purified by reverse-phase HPLC (50%MeOH/H₂O) to give the title compound3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylcyclohexyl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)propanoicacid (40 mg, 0.074 mmol, 47.1% yield) as a solid. LC-MS m/z 514.3(M+H)⁺, 1.35 min (ret. Time).

Example 133 Ammonium3-(3-((2-(1-cyclohexylethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

Ethyl 2-cyclohexylpropanoate

To a solution of ethyl 2-cyclohexylacetate (10 g, 58.7 mmol) intetrahydrofuran (THF) (100 mL) was added LiHMDS (70.5 mL, 70.5 mmol)slowly under nitrogen at −78° C. The reaction mixture was stirred at−78° C. for 1 h. Iodomethane (10.00 g, 70.5 mmol) solution in 50 ml ofTHF was added and the reaction stirred at ambient temperature for 1 h.Water (30 mL) was added and the mixture extracted with ethyl acetate(3×30 mL). The combined organic layer was dried over MgSO₄ andconcentrated under a stream of nitrogen at 50° C. to give the titlecompound ethyl 2-cyclohexylpropanoate (10 g, 48.8 mmol, 83% yield) whichwas carried to the next step without further purification. LC-MS m/z185.1 (M+H)⁺, 2.28 min (ret. time).

2-Cyclohexylpropan-1-ol

To a solution of ethyl 2-cyclohexylpropanoate (10 g, 54.3 mmol) intetrahydrofuran (THF) (10 mL) was added LiAlH₄ (4.12 g, 109 mmol) slowlyunder nitrogen at 0° C. The reaction mixture was stirred at 0° C. for0.5 h and allowed to warm to ambient temperature for 2 h. To thereaction was added 30 mL of water and extracted with ethyl acetate (3×30mL). The combined organic layer was dried over MgSO₄ and concentratedunder a stream of nitrogen at 50° C. The crude product was purified bysilica gel chromatography (hexane:ethyl acetate=10:1) to give the titlecompound 2-cyclohexylpropan-1-ol (7.2 g, 45.6 mmol, 84% yield) which wascarried to the next step without further purification. ¹H NMR (400 MHz,CDCl₃) δ=3.64-3.63 (m, 1H), 3.61-3.48 (m, 1H), 1.77-1.65 (m, 4H), 1.51(m, 1H), 1.36-1.13 (m, 10H).

2-Cyclohexylpropanal

To a solution of 2-cyclohexylpropan-1-ol (1 g, 7.03 mmol) indichloromethane (DCM) (40 mL), 200 mg silica gel was added, thesuspension was stirred at 25° C. for 5 min, then PCC (3.03 g, 14.06mmol) was added. The reaction mixture was stirred at 25° C. for 4 h. Thereaction mixture was filtered through celite and washed with ethylacetate (3×20 mL). The combined filtrate was concentrated and theresidue was purified by silica gel chromatography (petroleum ether/ethylacetate=22%) to give the title compound 2-cyclohexylpropanal (850 mg,5.58 mmol, 79% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ=9.65 (s,1H), 2.23-2.21 (m, 1H), 2.20-1.60 (m, 6H), 1.30-1.14 (m, 8H).

2-(1-Cyclohexylethyl)-1H-imidazole

To a solution of 2-cyclohexylpropanal (800 mg, 5.71 mmol) in methanol(12 mL) and water (3.00 mL), oxaldehyde (331 mg, 5.71 mmol) and ammoniahydrate (400 mg, 11.41 mmol) were added. The reaction mixture wasstirred at 0° C. to ambient temperature for 16 h. The reaction mixturewas concentrated and the residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=48%) to give the titlecompound 2-(1-cyclohexylethyl)-1H-imidazole (900 mg, 4.75 mmol, 83%yield) as yellow solid. LC-MS m/z 179.1 (M+H)⁺, 1.15 min (ret. time).

Ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(1000 mg, 2.72 mmol) in dichloromethane (DCM) (2.0 mL), SOCl₂ (0.238 mL,3.27 mmol) was added. The reaction mixture was stirred at 00° C. for 2h. The reaction mixture was concentrated to give the title compoundethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(1000 mg, 2.59 mmol, 95% yield) as an oil which was carried to the nextstep without further purification. LC-MS m/z 386.1 (M+H)⁺, 1.98 min(ret. time)

Ammonium3-(3-((2-(1-cyclohexylethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of 2-(1-cyclohexylethyl)-1H-imidazole (39.3 mg, 0.220mmol) in N,N-dimethylformamide (DMF) (10 mL) at 0° C. under N₂, NaH(10.57 mg, 0.264 mmol) was carefully added. After the reaction mixturewas stirred at 0° C. for 0.5 h, a solution of ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(85 mg, 0.220 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added andthe reaction mixture was stirred at 00° C. to 25° C. for 16 h. Thesolvent was evaporated and the residue was dissolved into 2 mL of water,acidified to pH 5 by 2N HCl in an ice bath. After part of the water wasconcentrated, the residue was purified by reverse-phase HPLC(CH₃CN/NH₄HCO₃/H2O=50%) to give the title compound3-(3-((2-(1-cyclohexylethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (38 mg, 0.076 mmol, 34.5% yield) as light yellow solid. LC-MS m/z500.2 (M+H)⁺, 1.35 min (ret. time).

Example 1343-(3-((1-(Cyclohexylmethyl)-1H-tetrazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, hydrochloride salt

4-Bromo-2-(chloromethyl)-1-methylbenzene

To a solution of (5-bromo-2-methylphenyl)methanol (5.4 g, 26.9 mmol) indichloromethane (DCM) (50 mL) was added SOCl₂ (3.92 mL, 53.7 mmol)slowly under nitrogen at 25° C. The reaction mixture was stirred at 25°C. for 4 h. Then it was concentrated to give the title compound4-bromo-2-(chloromethyl)-1-methylbenzene (5.45 g, 22.35 mmol, 83% yield)which was carried to the next step without further purification. LC-MSm/z 241.1 (M+Na)⁺, 1.84 min (ret. time).

2-(5-Bromo-2-methylphenyl)acetonitrile

To a solution of 4-bromo-2-(chloromethyl)-1-methylbenzene (4.3 g, 19.59mmol) in ethanol (20 mL) and water (5 mL) was added potassium cyanide(1.913 g, 29.4 mmol) slowly under nitrogen at ambient temperature. Thereaction mixture was stirred at 90° C. for 16 h. Water (10 mL) was addedand extracted with ethyl acetate (3×30 mL). The combined organic layerwas dried over MgSO₄ and concentrated under a stream of nitrogen at 50°C. to give the title compound 2-(5-bromo-2-methylphenyl)acetonitrile(4.3 g, 14.12 mmol, 72.1% yield) which was carried to the next stepwithout further purification. LC-MS m/z 210.0 (M+H)⁺, 1.66 min (ret.time)

2-(5-Bromo-2-methylphenyl)acetic acid

To a solution of 2-(5-bromo-2-methylphenyl)acetonitrile (5 g, 23.80mmol) in ethanol (50 mL) was added NaOH (23.80 mL, 143 mmol) slowlyunder nitrogen. The reaction mixture was stirred at ambient temperaturefor 18 hr. The solvent was evaporated and was acidified to pH 2 with 6 NHCl. The solid was filtered and dried with high vacuum to give the titlecompound 2-(5-bromo-2-methylphenyl)acetic acid (4.9 g, 19.25 mmol, 81%yield) which was carried to the next step without further purification.

LC-MS m/z 230.0 (M+H)⁺, 1.54 min (ret. time)

2-(5-Bromo-2-methylphenyl)-N-(cyclohexylmethyl)acetamide

To a solution of 2-(5-bromo-2-methylphenyl)acetic acid (4.1 g, 17.90mmol) in dichloromethane (DCM) (40 mL) was added oxalyl chloride (4.70mL, 53.7 mmol) slowly under nitrogen at 0° C. The reaction mixture wasstirred at ambient temperature for 2 h. Then it was concentrated anddissolved in 10 mL of DCM and added to cyclohexylmethanamine (3.04 g,26.8 mmol) and TEA (7.48 mL, 53.7 mmol) solution in 20 mL of DCM. Thereaction mixture was stirred at ambient temperature for 4 h afterwhich10 mL of water was added and the mixture extracted with ethyl acetate(3×30 mL). The combined organic layer was washed with 1 N HCl, brine anddried over MgSO₄, concentrated under a stream of nitrogen at 50° C. togive the title compound2-(5-bromo-2-methylphenyl)-N-(cyclohexylmethyl)acetamide (4.1 g, 12.01mmol, 67.1% yield) which was carried to the next step without furtherpurification. LC-MS m/z 324.1 (M+H)⁺, 1.79 min (ret. time)

5-(5-Bromo-2-methylbenzyl)-1-(cyclohexylmethyl)-1H-tetrazole

A solution of 2-(5-bromo-2-methylphenyl)-N-(cyclohexylmethyl)acetamide(3.1 g, 9.56 mmol) in toluene (50 mL) was treated with PCl₅ (3.98 g,19.12 mmol) slowly under nitrogen at 20° C. After the reaction mixturewas stirred at 20° C. for 4 h, TMSN₃ (3.17 mL, 23.90 mmol) was added andstirred at 20° C. for 16 h. Water (100 mL) was added and the mixtureextracted with ethyl acetate (3×100 mL). The combined organic layer waswashed with saturated NaHCO₃, brine and dried over MgSO₄, filtered andconcentrated. The crude product was purified by silica gelchromatography (hexane:ethyl acetate=4:1) to give the title compound5-(5-bromo-2-methylbenzyl)-1-(cyclohexylmethyl)-1H-tetrazole (1.5 g,4.12 mmol, 43.1% yield) as a white solid. LC-MS m/z 351.1 (M+H)⁺, 1.83min (ret. time)

1-(Cyclohexylmethyl)-5-(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-tetrazole

To a solution of5-(5-bromo-2-methylbenzyl)-1-(cyclohexylmethyl)-1H-tetrazole (1.5 g,4.29 mmol) in 1,4-dioxane (50 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.309 g,5.15 mmol), potassium acetate (0.632 g, 6.44 mmol) andPdCl₂(dppf)-CH₂Cl₂ adduct (0.175 g, 0.215 mmol) slowly under nitrogen atambient temperature. The reaction mixture was stirred at 90° C. for 16h. Water (50 mL) was added and the mixture extracted with ethyl acetate(3×50 mL). The combined organic layer was dried over MgSO₄, concentratedunder a stream of nitrogen at 50° C. The crude product was purified bysilica gel chromatography (hexane:ethyl acetate=4:1) to give the titlecompound1-(cyclohexylmethyl)-5-(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-tetrazole(1.1 g, 2.498 mmol, 58.2% yield). LC-MS m/z 397.3 (M+H)⁺1.90 min (ret.time)

Ethyl3-(3-((1-(cyclohexylmethyl)-1H-tetrazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of (E)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (300 mg, 1.223mmol) in 1,4-dioxane (30 mL) was added(2R,3R)-butane-2,3-diylbis(diphenylphosphine) (57.4 mg, 0.135 mmol),1-(cyclohexylmethyl)-5-(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-tetrazole(970 mg, 2.446 mmol), (Rh(nbd)Cl)₂ (56.4 mg, 0.122 mmol) and KOH (3.67mL, 3.67 mmol) slowly under nitrogen at 25° C. The reaction mixture wasstirred at 25° C. for 16 h. Water (30 mL) was added and the mixtureextracted with ethyl acetate (3×60 mL). The combined organic layer wasdried over MgSO₄ and concentrated under a stream of nitrogen at 50° C.The crude product was purified by silica gel chromatography(hexane:ethyl acetate=1:1) to give the title compound ethyl3-(3-((1-(cyclohexylmethyl)-1H-tetrazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(350 mg, 0.645 mmol, 52.7% yield) as an oil. LC-MS m/z 516.3 (M+H)⁺,1.75 min (ret. time)

3-(3-((1-(Cyclohexylmethyl)-1H-tetrazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, hydrochloride salt

To a solution of ethyl3-(3-((1-(cyclohexylmethyl)-1H-tetrazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(350 mg, 0.679 mmol) in tetrahydrofuran (THF) (5 mL) was added LiOH(65.0 mg, 2.72 mmol) in water (5.00 mL) slowly under nitrogen at 50° C.The reaction mixture was stirred at 50° C. for 16 h. Then it wasacidified to pH 3 with 1 N HCl and extracted with ethyl acetate (3×10mL). The combined organic phase was dried over MgSO₄ and concentrated.The crude product was purified by silica gel chromatography(hexane:ethyl acetate=4:1) to give the title compound3-(3-((1-(cyclohexylmethyl)-1H-tetrazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (150 mg, 0.292 mmol, 43.1% yield) as a white solid. LC-MS m/z 488.3(M+H)⁺, 1.60 min (ret. time)

Example 1353-(3-((2-(Cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(4-fluoro-2-methylphenyl)propanoicacid

(E)-Ethyl 3-(4-fluoro-2-methylphenyl)acrylate

To a solution of ethyl 2-(diethoxyphosphoryl)acetate (19.48 g, 87 mmol)in tetrahydrofuran (THF) (100 mL) at 0° C. was added sodium hydride(3.47 g, 87 mmol)) in small portions. After 15 min,4-fluoro-2-methylbenzaldehyde (10 g, 72.4 mmol) in THF (20 mL) was addedslowly. The mixture sitrred at room temperature for 30 min. Then NH₄Cl(sat. aq.) was added and the solution was extracted with EtOAc (50mL×3). The combined organic layer was washed with brine (10 mL×3), dried(Na₂SO₄), filtered and concentrated. The residue was purified withCombiflash (PE:EA=10%) to give the title compound (E)-ethyl3-(4-fluoro-2-methylphenyl)acrylate (13 g, 58.7 mmol, 81% yield) as acolorless oil. LCMS m/z: 209 (M+H)+, 1.78 min (ret. time),

Ethyl3-(4-fluoro-2-methylphenyl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

To a solution of (E)-ethyl 3-(4-fluoro-2-methylphenyl)acrylate (5.8 g,27.9 mmol) in 1,4-dioxane (60 mL) and water (30 mL) was added(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(13.82 g, 55.7 mmol), TEA (7.76 mL, 55.7 mmol). It was stirred for 5 minand then added chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.687 g,1.393 mmol) under the protection of nitrogen. The reaction mixture wasstirred at 90° C. for 2 h. After cooling to 25° C., the mixture wasquenched with water (10 mL), extracted with EtOAc(3×80 mL). The combinedorganic layer was washed with water (2×5 mL) and brine (2×5 mL), dried(Na₂SO₄), filtered and concentrated. The residue was purified withCombiflash (sillic gel column, 40 g, PE:EA=15%) to give the titlecompound (5.9 g, 16.43 mmol, 59.0% yield) as colorless oil. LCMS m/z 353(M+Na)⁺2.04 min (ret.time)

Ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(4-fluoro-2-methylphenyl)propanoate

To a solution of ethyl3-(4-fluoro-2-methylphenyl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(330 mg, 0.999 mmol) in dichloromethane (DCM) (6.0 mL), SOCl₂ (0.087 mL,1.199 mmol) was added at 00° C. The reaction mixture was stirred at for2 h at 0° C. Then it was concentrated to give the title compound ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(4-fluoro-2-methylphenyl)propanoate(300 mg, 0.826 mmol, 83% yield) as colorless oil which was carried tothe next step without further purification. LC-MS m/z 371.1 (M+Na)⁺,1.88 min (ret. time)

Ethyl3-(3-((2-(cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(4-fluoro-2-methylphenyl)propanoate

To a solution of 2-(cyclohexylmethyl)-1H-imidazole (141 mg, 0.860 mmol)in tetrahydrofuran (THF) (3 mL) at 0° C. under N₂, NaH (34.4 mg, 0.860mmol) was carefully added. The reaction mixture was stirred at 0° C. for0.5 h. Then a solution of ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(4-fluoro-2-methylphenyl)propanoate(300 mg, 0.860 mmol) in tetrahydrofuran (THF) (3 mL) was added and themixture was stirred at 0 to 25° C. for 16 h. The reaction mixture wasquenched with saturated NH₄Cl solution (10 mL), and extracted with ethylacetate (3×30 mL). The combined organic layer was washed with water (2×8mL) and brine (2×8 mL), dried over (Na₂SO₄) and concentrated. Theresidue was purified with silica gel chromatography (petroleumether/ethyl acetate=5%) to give the title compound ethyl3-(3-((1-(cyclohexylmethyl)-1H-imidazol-2-yl)methyl)-4-methylphenyl)-3-(4-fluoro-2-methylphenyl)propanoate(160 mg, 0.302 mmol, 35.1% yield) as colorless oil. LC/MS m/z 477.2(M+H)⁺1.53 min (ret. time)

3-(3-((2-(Cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(4-fluoro-2-methylphenyl)propanoicacid

To a solution of ethyl3-(3-((2-(cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(4-fluoro-2-methylphenyl)propanoate(160 mg, 0.336 mmol) in methanol (4 mL) and water (1.000 mL) at 25° C.,sodium hydroxide (26.9 mg, 0.671 mmol) was added. The reaction mixturewas stirred at 25° C. for 1 h. The solvent was removed and the residuewas dissolved into 2 mL of water, acidified to pH 4 by 2 N HCl at 0° C.to precipitate a white solid. The crude was purified by reverse-phaseHPLC (CH₃CN/H₂O with 0.05% NH₃H₂O) to give the title compound3-(3-((2-(cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(4-fluoro-2-methylphenyl)propanoicacid (70 mg, 0.156 mmol, 46.5% yield) as a pale white solid. LC-MS m/z449.2 (M+H)⁺, 1.44 min (ret. time)

Example 1363-(3-((4-(Cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

5-(Cyclohexylmethyl)-1H-imidazole

TOSMIC (696 mg, 3.57 mmol) was added to a saturated solution of ammoniain methanol (2.0 ml). After stirring at ambient temperature for 1 h,2-cyclohexylacetaldehyde (300 mg, 2.377 mmol) was added over 2 min.After the reaction mixture was stirred at refluxed temperature for 3 h,it was poured into cold 1 N hydrochloric acid (10 mL) and washed withhexane. The aqueous layer was basified with 1.0 N aqueous sodiumhydroxide and extracted with ether (3×50 mL). The combined organic layerwas washed with brine (10 mL), dried over magnesium sulfate, filteredand concentrated. The crude product was purified by silica gelchromatography eluting with 5-10% methanol in methylene chloride to givethe title compound 5-(cyclohexylmethyl)-1H-imidazole (60 mg, 0.365 mmol,15.37% yield). LC-MS m/z 165.2 (M+H)⁺, 1.17 min (ret. Time).

Ethyl3-(3-((4-(cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of 5-(cyclohexylmethyl)-1H-imidazole (50 mg, 0.304 mmol)in N,N-dimethylformamide (DMF) (3.0 mL), DIPEA (0.053 mL, 0.304 mmol)was added. Then ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(117 mg, 0.304 mmol) was added to the reaction. The reaction mixture wasstirred at 100° C. for 4 h. Then it was purified by reverse-phase HPLC(50% MeOH/H₂O) to give the title compound ethyl3-(3-((4-(cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(85 mg, 0.165 mmol, 54.4% yield) as a solid. LC-MS m/z 514.3 (M+H)⁺,1.42 min (ret. time)

3-(3-((4-(Cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

To a solution of ethyl3-(3-((4-(cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(85 mg, 0.165 mmol) in methanol (5 mL), NaOH (19.86 mg, 0.496 mmol) inH₂O (1 ml) was added. The reaction mixture was stirred at 20° C. for 4h. The solvent was evaporated and the residue was neutralized with 1NHCl to pH 3. The crude product was purified by reverse-phase HPLC (50%MeOH/H₂O) to give the title compound3-(3-((4-(cyclohexylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (50 mg, 0.098 mmol, 59.1% yield) as a solid. LCMS m/z 486.2 (M+H)⁺,1.34 min (ret. Time)

Example 1373-(3-((3-(Cyclohexylmethyl)-5-methyl-1H-1,2,4-triazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

2-Cyclohexylacetohydrazide

To a solution of methyl 2-cyclohexylacetate (10 g, 64.0 mmol) inmethanol (60 mL) was added hydrazine monohydrate (12.44 mL, 256 mmol).The reaction mixture was stirred at 70° C. for 20 h. After it was cooledto ambient temperature, 200 mL of water was added. The solid wasfiltered to give the title compound 2-cyclohexylacetohydrazide (6.8 g,42.3 mmol, 66.0% yield) as white solid. LCMS m/z 157.2 (M+H)⁺, 1.47 min(ret. Time)

3-(Cyclohexylmethyl)-5-methyl-1H-1,2,4-triazole

A mixture of 2-cyclohexylacetohydrazide (1 g, 6.40 mmol),ethanethioamide (1.924 g, 25.6 mmol), pyridine (10 mL) and 1-butanol(50.0 mL) were stirred at 130° C. for 20 h. The reaction mixture wasconcentrated. The crude product was purified by reverse-phase HPLC togive the title compound 3-(cyclohexylmethyl)-5-methyl-4H-1,2,4-triazole(400 mg, 2.072 mmol, 32.4% yield). LC-MS m/z 180.2 (M+H)⁺, 1.43 min(ret. time)

Ethyl3-(3-((3-(cyclohexylmethyl)-5-methyl-1H-1,2,4-triazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of 3-(cyclohexylmethyl)-5-methyl-4H-1,2,4-triazole (55.7mg, 0.311 mmol) in N,N-dimethylformamide (DMF) (2 mL) was added sodiumhydride (12.44 mg, 0.311 mmol) under the protection of nitrogen at 0° C.The reaction mixture was stirred for 20 min at 00° C. and ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(100 mg, 0.259 mmol) was added to the mixture. Then it was stirred at10° C. for 1 h. Water (20 mL) was added and the mixture extracted withEtOAc (3×20 mL). The combined organic layer was dried over MgSO₄ andconcentrated to give the title compound ethyl3-(3-((3-(cyclohexylmethyl)-5-methyl-4H-1,2,4-triazol-4-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(115 mg, 0.183 mmol, 70.6% yield) which was carried to the next stepwithout further purification. LC-MS m/z 529.3 (M+H)⁺, 1.96 (ret. time)

3-(3-((3-(Cyclohexylmethyl)-5-methyl-1H-1,2,4-triazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

To a solution of ethyl3-(3-((3-(cyclohexylmethyl)-5-methyl-4H-1,2,4-triazol-4-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(110 mg, 0.208 mmol) in tetrahydrofuran (THF) (2 mL) was added asolution of sodium hydroxide (33.3 mg, 0.832 mmol) in water (2.0 mL).The reaction mixture was stirred at 10° C. for 16 h. 1N HCl was added topH 3. The crude product was purified by reverse-phase HPLC to give thetitle compound3-(3-((3-(cyclohexylmethyl)-5-methyl-1H-1,2,4-triazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (20 mg, 0.039 mmol, 18.54% yield). LC-MS m/z 501.0 (M+H)⁺, 1.66(ret. time)

Example 1383-(3-((2-((1,4-Oxazepan-4-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

To a solution of 4-((1H-imidazol-2-yl)methyl)-1,4-oxazepane (43.5 mg,0.240 mmol) in N,N-dimethylformamide (DMF) (1 mL) at 25° C. was addedNaH (16.00 mg, 0.400 mmol). The mixture was stirred at 25° C. for 40min. Methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(80 mg, 0.200 mmol) in N,N-dimethylformamide (DMF) (1 mL) was added andthe mixture was stirred for 21 h. It was quenched with saturated NH₄Cland extracted with ethyl acetate twice. The combined organic layer wasconcentrated to give the crude product. The reaction mixture waspurified by silica gel chromatography (product eluted at 100% ethylacetate). Desired fractions were concentrated and re-dissolved in MeOH(2 mL). LiOH (0.600 mL, 1.200 mmol) was added and the reaction washeated in a Biotage microwave at high absorption for 3 h at 120° C. Itwas acidified with 6 N HCl to pH˜1. 0.5 mL DMSO was added andconcentrated. The crude product was purified by reverse-phase HPLC (with0.1% TFA condition) to give the title compound (53 mg, 0.100 mmol, 49.9%yield) (69-B1). LC-MS m/z 531.1 (M+H)⁺, 0.66 min (ret. time)

The compounds in Table 15 were prepared by a method similar to the onedescribed for the preparation of3-(3-((2-((1,4-oxazepan-4-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid. As is appreciated by those skilled in the art, these analogousexamples may involve variations in general reaction conditions.

TABLE 15 LCMS Retention Ex # Structure Name [M + H]⁺ Time (min) Example139

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-2,2-dimethyl-3-(4-methyl-3-((2-((4- methylpiperidin-1- yl)methyl)-1H- imidazol-1-yl)methyl)phenyl) propanoic acid 529.5 0.71 Example 140

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5- yl)-3-(3-((2-((4-ethylpiperidin-1- yl)methyl)-1H-imidazol- 1-yl)methyl)-4-methylphenyl)-2,2- dimethylpropanoic acid, formic acid salt 543.5 0.82Example 141

3-(3-((2-(Azepan-1- ylmethyl)-1H-imidazol-1- yl)methyl)-4-methylphenyl)-3-(1,4- dimethyl-1H- benzo[d][1,2,3]triazol-5- yl)-2,2-dimethylpropanoic acid, trifluoroacetic acid salt 529.5 0.72 Example 142

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5- yl)-2,2-dimethyl-3-(4-methyl-3-((2- (morpholinomethyl)-1H- imidazol-1- yl)methyl)phenyl)propanoic acid, trifluoroacetic acid salt 517.4 0.75 Example 143

3-(3-((2- (Cyclohexylmethyl)-1H- imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4- dimethyl-1H- benzo[d][1,2,3[triazol-5- yl)-2,2-dimethylpropanoic acid, trifluoroacetic acid salt 514.4 0.90 Example 144

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-2,2-dimethyl-3-(4-methyl-3-((2-(((R)- 2-methylmorpholino) methyl)-1H-imidazol-1-yl)methyl)phenyl) propanoic acid, trifluoroacetic acid salt 531.4 0.70Example 145

3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-2,2-dimethyl-3-(4-methyl-3-((2- ((tetrahydro-2H-pyran- 4-yl)methyl)-1H- imidazol-1-yl)methyl)phenyl) propanoic acid, trifluoroacetic acid salt 516.5 0.69Example 146

3-(3-((2- (Cycloheptylmethyl)- 1H-imidazol-1-yl)methyl)-4-methylphenyl)- 3-(1,4-dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)propanoic acid, formic acid salt 500.30 1.86 Example 147

3-(3-((2-(Azepan-1- ylmethyl)-1H-imidazol- 1-yl)methyl)-4-methylphenyl)-3-(1,4- dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)propanoic acid, formic acid salt 501.4 0.66 Example 148

3-(3-((2- (Cyclopentylmethyl)-1H- imidazol-1-yl)methyl)-4-methylphenyI)-3-(1,4- dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)propanoic acid 472.25 1.75 Example 149

3-(3-((2-((4,4- Difluoropiperidin-1- yl)methyl)-1H-imidazol-1-yl)methyl)-4- methylphenyl)-3-(1,4- dimethyl-1H-benzo[d][1,2,3]triazol- 5-yl)propanoic acid 501.4 0.66 Example 150

(S)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5- yl)-2,2-dimethyl-3-(4-methyl-3-((2-(piperidin- 1-ylmethyl)-1H-imidazol- 1-yl)methyl)phenyl)propanoic acid 515.6 0.72 Example 151

3-(3-((2-(Azepan-1- ylmethyl)-1H-imidazol- 1-yl)methyl)-4-methylphenyl)-3-(1,4- dimethyl-1H-benzo- [d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid, 0.3 formic acid salt 529.3 0.87

Example 152(3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid, trifluoroacetic acid salt

(3R)-Benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2-methylpropanoate

To a solution of 1-((1H-imidazol-2-yl)methyl)-4-ethylpiperidine (36.8mg, 0.190 mmol) in N,N-dimethylformamide (DMF) (1 mL) at 0° C. was addedNaH (8.31 mg, 0.208 mmol). The mixture was stirred at 0° C. for 40 min.(3R)-benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2-methylpropanoate(74 mg, 0.120 mmol, 69.1% yield) in N,N-dimethylformamide (DMF) (1 mL)was added and the mixture was stirred for 21 h. More NaH (8.31 mg, 0.208mmol) was added and stirred for 5 h. It was quenched with saturatedNH₄Cl, extracted with ethyl acetate twice. The combined organic layerwas concentrated to give the crude product. The crude product waspurified by silica gel chromatography. The desired fractions wereconcentrated to give the title compound (74 mg, 0.120 mmol, 69.1%yield). LC-MS m/z 619.4 (M+H)⁺, 1.06 min (ret. time)

(3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid, trifluoroacetic acid salt

A solution of (3R)-benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2-methylpropanoate(74 mg, 0.120 mmol) in ethyl acetate (6 mL) was passed through H-Cube(cartridge: Pd/C, 1 mL/min, 25° C.) for 2 h. The solvent was removedunder reduced pressure and the sample was purified by reverse-phase HPLC(with 0.1% TFA condition) to give the title compound (26.2 mg, 0.050mmol, 41.4% yield). LC-MS m/z 529.3 (M+H)⁺, 0.77 min (ret. time

Example 1533-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-(pyrrolidin-1-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoicacid, formic acid salt

2-Cyclopentylethanol

To a solution of 2-cyclopentylacetic acid (5 g, 39.0 mmol) intetrahydrofuran (THF) (10 mL) at 0° C. was added a solution of BH₃.DMS(39.0 mL, 78 mmol) in toluene dropwise. It was stirred at ambienttemperature for 16 h. The reaction mixture was cooled to 0° C. andquenched with methanol (10 mL) dropwise. The reaction mixture wasstirred at ambient temperature for 3 h and then concentrated. The cruderesidue was diluted with ethyl acetate (50 mL) and washed with 1N HCl(10 mL), brine solution (10 mL) and dried over anhydrous Na₂SO₄,filtered and concentrated to give the title compound (4 g, 35.0 mmol,90% yield). 1H NMR (400 MHz, cdcl3) δ=3.66 (t, J=6.9 Hz, 2H), 1.91-1.72(m, 3H), 1.64-1.45 (m, 6H), 1.19-1.03 (m, 2H).

2-Cyclopentylacetaldehyde

To a solution of 2-cyclopentylethanol (4 g, 35.0 mmol) indichloromethane (DCM) (50 mL) at 0° C. was added Dess-Martin periodinane(22.29 g, 52.5 mmol). It was stirred at ambient temperature for 4 h. Thereaction mixture was filtered through celite. The filtrate wasconcentrated to give the title compound (2 g, 17.83 mmol, 50.9% yield)as liquid. 1H NMR (400 MHz, CDCl₃) δ=9.76 (t, J=2.2 Hz, 1H), 2.44 (dd,J=2.1, 7.1 Hz, 2H), 2.34-2.22 (m, 1H), 1.95-1.80 (m, 2H), 1.71-1.45 (m,4H), 1.23-1.07 (m, 2H).

2-(Cyclopentylmethyl)-1H-imidazole

To a solution of 2-cyclopentylacetaldehyde (2 g, 17.83 mmol) in water(20 mL) at ambient temperature was added glyoxal hydrate (0.749 g, 3.57mmol) and ammonia (0.386 mL, 17.83 mmol). The reaction was stirred atambient temperature for 18 h. The reaction mixture was diluted withwater and extracted with twice DCM. The organic layer was dried underanhydrous Na₂SO₄, filtered and concentrated to give the crude compound.It was purified by silica gel chromatography to give the title compound(400 mg, 2.428 mmol, 13.62% yield) as liquid. LC-MS m/z 151.15 (M+H)⁺,2.386 min (ret. time)

Ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-(pyrrolidin-1-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoate

To a solution of 2-(pyrrolidin-1-ylmethyl)-1H-imidazole (37.6 mg, 0.249mmol) in N,N-dimethylformamide (DMF) (1 mL) at 25° C. was added NaH(10.78 mg, 0.270 mmol). The mixture was stirred at 25° C. for 40 min.Ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(80 mg, 0.207 mmol) in N,N-dimethylformamide (DMF) (1 mL) was added andthe mixture was stirred for 21 h. It was quenched with saturated NH₄Cland extracted with ethyl acetate twice. The combined organic layer wasconcentrated and purified by reverse-phase HPLC (with 0.1% TFAcondition) to give the title compound (80 mg, 0.160 mmol, 77% yield).LC-MS m/z 501.4 (M+H)⁺, 0.75 min (ret. time)

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-(pyrrolidin-1-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoicacid, formic acid salt

A mixture of ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-(pyrrolidin-1-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoate(77 mg, 0.154 mmol) and 2M LiOH (0.461 mL, 0.923 mmol) in methanol (2mL) was heated in a Biotage microwave at high absorption for 30 minutesat 80° C. It was acidified with 6N HCl and 0.5 mL DMSO was added. It wasconcentrated and purified with preparative HPLC under acidic conditionsto give the title compound (29.6 mg, 0.057 mmol, 37.1% yield). LC-MS m/z473.4 (M+H)⁺, 0.61 min (ret. time)

Example 1543-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-(piperidin-1-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoic acid,trifluoroacetic acid salt

Ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

Thionyl chloride (0.397 mL, 5.44 mmol) was added to a solution of ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(1 g, 2.72 mmol) in dichloromethane (DCM) (5.44 mL) at ambienttemperature and stirred for 1 hour. The solution was concentrated invacuo to give the title compound (1.1 g, 2.85 mmol, 105% yield). LC/MS:m/z 386.1 (M+H)⁺, 1.13 min (ret. time).

3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2-(piperidin-1-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoic acid,trifluoroacetic acid salt

Sodium hydride (24.88 mg, 0.622 mmol) was added to a solution of1-((1H-imidazol-2-yl)methyl)piperidine (34.3 mg, 0.207 mmol) inN,N-dimethylformamide (DMF) (4.146 mL) at 0° C. The solution was allowedto stir for 30 minutes before a solution of ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(80 mg, 0.207 mmol) in N,N-dimethylformamide (DMF) (4.146 mL) was added.The reaction was complete after 48 hours. The solution was quenched withsaturated ammonium chloride (5 mL) and extracted with ethyl acetate(3×10 mL), washed (brine), and solvent removed in vacuo. The aqueousfraction was concentrated and redissolved in a 4:1isopropanol/dichloromethane and filtered. The filtrate was concentratedand the crude product was purified by reverse-phase HPLC (with 0.1% TFA)to give the title compound (26.2 mg, 0.044 mmol, 21.04% yield). LC/MS:m/z 487.1 (M+H)⁺, 0.7 min (ret. time).

Example 1553-(3-((2-(7-Azabicyclo[2.2.1]heptan-7-ylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid, trifluoroacetic acid salt

To a solution of methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(0.100 g, 0.195 mmol) in acetonitrile (4 mL) was added7-((1H-imidazol-2-yl)methyl)-7-azabicyclo[2.2.1]heptane (0.035 g, 0.195mmol) and DIEA (0.136 mL, 0.780 mmol) and stirred at room temperaturefor 18 h. The reaction was heated to 55° C. for 4 h. The solvent wasconcentrated and the residue was redissolved in N,N-dimethylformamide(DMF) (4.00 mL). Sodium hydride (0.023 g, 0.585 mmol) was added andstirred at 45° C. for 18 h. The solvent was then concentrated. Theresidue was redissolved in methanol (1 mL) tetrahydrofuran (THF) (1 mL)and water (1 mL LiOH (0.019 g, 0.780 mmol was added and stirred at roomtemperature for 22 h. The reaction was heated to 45° C. after whichadditional LiOH (0.023 g, 0.975 mmol was added and heating was continuedfor 6 h. The reaction mixture was then transferred to a microwavereaction vial and heated to 150° C. for 1 hour. The solvent was thenconcentrated, the residue was redissolved in DMSO and acidified withTFA. The residue was purified by reverse phase preparative HPLC underneutral conditions and then acidic conditions to provide the titlecompound. (0.045 g, 35% yield) LC-MS m/z 526 (M+H)⁺, 0.68 min (ret.time).

Example 1563-(3-((2-(8-Azabicyclo[3.2.1]octan-8-ylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid, trifluoroacetic acid salt

To a solution of methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(0.100 g, 0.195 mmol) in acetonitrile (4 mL) was added8-((1H-imidazol-2-yl)methyl)-8-azabicyclo[3.2.1]octane (0.037 g, 0.195mmol) and DIEA (0.136 mL, 0.780 mmol) and stirred at room temperaturefor 18 h. The solvent was concentrated and the residue was redissolvedin N,N-dimethylformamide (DMF) (4.00 mL). Sodium hydride (0.023 g, 0.585mmol) was added and stirred at 45° C. for 18 h. The solvent was thenconcentrated. The residue was redissolved in methanol (1 mL),tetrahydrofuran (THF) (1 mL), and water (1 mL) and added LiOH (0.019 g,0.780 mmol) and heated to 45° C. for 25 h. The reaction mixture was thentransferred to a microwave reaction vial and heated to 150° C. for 1hour. The solvent was then concentrated, the residue was redissolved inDMSO and acidified with TFA. The residue was purified by reverse phasepreparative HPLC under neutral conditions and then acidic conditions toprovide the title compound. (0.065 g, 50 yield %) LC-MS m/z 541 (M+H)⁺,0.71 min (ret. time).

Example 157(3R)-3-(3-((3-(1H-Pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (isomer 1)

tert-Butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate

tert-Butyl 3-hydroxypiperidine-1-carboxylate (5 g, 24.84 mmol) wasdissolved in dichloromethane (83 mL). Then, triethylamine (5.17 mL, 37.3mmol) was added and the mixture was cooled to 0° C. (ice/water bath).Following this, methanesulfonyl chloride (2.115 mL, 27.3 mmol) was addedand the reaction was allowed to stir for 16 h as the ice bath expired.The organic layer was washed with saturated aqueous NH₄Cl solution (2×10mL), water (10 mL), saturated NaCl solution (2×10 mL), dried (MgSO₄),filtered and concentrated to yield the crude title compound as a yellowoil (6.6521 g, 96%) which was used in the next step without furtherpurification. LC-MS m/z 280.1 (M+H)⁺, 0.80 (ret. time).

tert-Butyl 3-(1H-pyrazol-1-yl)piperidine-1-carboxylate

1H-Pyrazole (0.975 g, 14.32 mmol) was dissolved in DMF (35.8 mL). Themixture was cooled to 0° C. (ice/water bath). Following this, sodiumhydride (60% in mineral oil) (0.573 g, 14.32 mmol) was added. Themixture was stirred at ambient temperature for 15 min after whichtert-butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate (2 g, 7.16mmol) in DMF (5 mL) was added. The reaction mixture was allowed to stirat ambient temperature for 72 h. A portion (approximately half) of thereaction mixture was heated in a microwave at 100° C. (high absportion)for 1 h. The two reaction mixtures (ambient temperature conditions andmicrowave conditions) were combined and quenched by adding saturatedaqueous NH₄Cl solution (5 mL). The reaction mixture was concentrated.The residue was dissolved in ethylacetate (50 mL) and water (10 mL). Theorganic layer was washed with water (3×10 mL), saturated NaCl solution(10 mL) and dried (MgSO₄) to give the crude material. The crude materialwas combined with crude material from another batch prepared in asimilar manner to that reported here (the other batch was run on a 1 gscale of the mesylate). The combined crude products were purified on asilica cartridge (40 g) with a Combiflash Companion, eluting at 40mL/min with a gradient running from 100% hexanes to 100% ethyl acetateover 45 min to give the title compound as a colorless oil (0.5808 g,21.5% overall). LC-MS m/z 252.1 (M+H)⁺, 0.85 (ret. time).

3-(1H-Pyrazol-1-yl)piperidine, hydrochloride

tert-Butyl 3-(1H-pyrazol-1-yl)piperidine-1-carboxylate (0.5808 g, 2.311mmol) was dissolved in 1,4-dioxane (5 mL). Following this, 4 M HCl indioxane (3.47 mL, 13.87 mmol) was added and the reaction mixture wasstirred at ambient temperature. After 2 h, additional 4 M HCl in dioxane(3 mL, 12.00 mmol) and 1,4-dioxane (3 mL) were added and the reactionwas stirred ambient temperature for an additional 16 h (overall 18 h ofstirring). The solvent was removed under reduced pressure to yield crude3-(1H-pyrazol-1-yl) piperidine, hydrochloride as a white solid (0.3727g, 86% yield) which was used in the next step without furtherpurification. LC-MS m/z 151.9 (M+H)⁺, 0.30 (ret. time).

(3R)-Ethyl3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

3-(1H-Pyrazol-1-yl) piperidine, hydrochloride (0.099 g, 0.527 mmol) wasadded to acetonitrile (2.174 mL). Then, DIEA (0.608 mL, 3.48 mmol) wasadded. Following this, (R)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (0.1678 g, 0.435 mmol) was added. The reaction mixture washeated in a microwave at 80° C. (high absorption) for 1 h. The solventwas removed to yield crude (3R)-ethyl 3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (0.4632 g, 213%) which was used in the next step withoutfurther purification. LC-MS m/z 501.3 (M+H)⁺, 0.77 (ret. time).

(3R)-3-(3-((3-(1H-Pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (isomer 1)

(3R)-Ethyl3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(0.4632 g, 0.925 mmol) was dissolved in methanol (3.08 mL). Then, 1 MNaOH (3.70 mL, 3.70 mmol) was added and the reaction mixture was heatedin a microwave at 80° C. (high absorption) for 20 min. The mixture wasacidified to pH 4-5 (1 M HCl). The crude mixture of diastereomers waspurified by achiral reverse phase preparative HPLC under formic acidconditions (0.1%). Relevant fractions were collected and concentrated.The purified mixture of diastereomers was then separated by chiral SFC(supercritical fluid chromatography). Relevant fractions wereconcentrated to yield isomer 1 (0.0447 g, 10.22% yield). LC-MS m/z 473.4(M+H)⁺, 0.63 (ret. time).

Example 158(3R)-3-(3-((3-(1H-Pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (isomer 2)

This is the other isomer (isomer 2) obtained from the diastereomericseparation of(3R)-3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid. Relevant fractions resulting from the above SFC separation werecombined to yield isomer 2 (0.0402 g, 9.19%). LC-MS m/z 473.4 (M+H)⁺,0.61 (ret. time).

The compound in Table 16 was prepared by a method similar to the onedescribed for the preparation of(3R)-3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (isomer 1) from (S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl).As is appreciated by those skilled in the art, this analogous examplemay involve variations in general reaction conditions.

TABLE 16 LCMS Retention Ex # Structure Name [M + H]⁺ Time (min) Example159

(3S)-3-(3-((3-(1H-Pyrazol- 1-yl)piperidin-1- yl)methyl)-4-methylphenyl)-3-(1,4- dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)propanoic acid (isomer 1) 473.4 0.62

Example 1603-(3-((3-(1H-Pyrazol-1-yl)piperidin-1-yl)methyl)-4-chlorophenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt

(5-Bromo-2-chlorophenyl)methanol

5-bromo-2-chlorobenzoic acid (2.5 g, 10.62 mmol) was dissolved in THF(53.1 mL) and the mixture was stirred at ambient temperature undernitrogen. Then, BH₃.THF (1.0 M in THF) (26.5 mL, 26.5 mmol) was addedslowly and the light yellow reaction mixture was stirred at ambienttemperature for 22 h. Ethanol (2 mL) was added slowly to the reactionmixture followed by water (4 mL). The mixture was diluted with water (20mL) and ethyl acetate (35 mL). More water (10 mL; 30 mL overall) wasadded. The aqueous layer was extracted with ethyl acetate (2×20 mL).Combined organic extracts were washed with a saturated aqueous solutionof NaHCO₃ (2×10 mL), saturated aqueous NaCl (10 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure to yield the crudeproduct. This crude material was recrystallized from dichloromethane,and the filtrate resulting from the recrystallization was concentratedand purified on a silica cartridge (40 g) with a Combiflash Companion,eluting at 40 mL/min with a gradient running from 100% hexanes to 40%ethyl acetate over 20 min. The pure products resulting fromrecrystallization and silica gel purification were combined to give thetitle compound as a white solid (1.6319 g, 69.4%). LC-MS m/z 203.0(M−OH)⁺, 0.79 (ret. time).

(2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol

(5-bromo-2-chlorophenyl) methanol (0.5 g, 2.258 mmol) was dissolved inDMF (9 mL). Then, bis(pinacolato)diboron (0.688 g, 2.71 mmol) was addedand the mixture was stirred. Potassium acetate (0.665 g, 6.77 mmol) wasadded quickly followed by PdCl₂ (dppf) (0.050 g, 0.068 mmol). Thereaction mixture was heated via microwave at 100° C. (high absorption)for 1 h. This procedure was performed two more times to give twoadditional batches prepared in a similar manner to that reported here.Material from all three batches was combined and the combined reactionmixture was concentrated. The residue was taken up in ethyl acetate (100mL) and filtered through a short pad of celite (1.5 g). The resultingblack solids were discarded. The filtrate was transferred into aseparatory funnel and washed with water (4×10 mL gently). The organiclayer was then washed with saturated NaCl solution (10 mL), dried(MgSO₄) and filtered. An initial attempt to purify the combined crudematerial on silica gel with a Combiflash Companion (40 g column, 40mL/min flow rate, 100% hexanes to 50% ethyl acetate gradient over 23min) did not produce clean product. Fractions were recombined and thecrude material was adsorbed onto isolute and repurified on a silicacartridge (40 g) with a Combiflash Companion, eluting at 40 mL/min witha gradient running from 100% hexanes to 60% acetone over 45 min to yieldthe title compound as a white solid (0.6382 g, 40.2%). LC-MS m/z 251.0(M-OH)⁺, 0.97 (ret. time).

Ethyl3-(4-chloro-3-(hydroxymethyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a suspension of(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(1.098 g, 4.09 mmol), (E)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (3.31 g, 13.49mmol), and chloro(1,5-cyclooctadiene)rhodium(I)dimer (0.202 g, 0.409mmol) in water (24 mL) and 1,4-dioxane (9 mL) at ambient temperature wasadded triethylamine (1.140 mL, 8.18 mmol). The mixture was heated to 75°C. for 2 h then 95° C. for 2.5 h. The reaction mixture was allowed tocool to ambient temperature. The mixture was diluted with ethyl acetate(40 mL) and water (10 mL). The organic layer was washed gently withwater (10 mL), saturated NaCl solution (10 mL), dried (MgSO₄), filtered,and concentrated. An initial attempt to purify the crude material onsilica gel with a Combiflash Companion (40 g column, 40 mL/min flowrate, 100% hexanes to 100% ethyl acetate gradient over 80 min) did notproduce clean product. Fractions were recombined and the crude materialwas adsorbed onto isolute and repurified on a silica cartridge (24 g)with a Combiflash Companion, eluting at 30 mL/min with a gradientrunning from 100% hexanes to 50% 3:1 ethyl acetate:ethanol over 65 minto yield the title compound as a light brown solid (0.6382 g, 40.2%).LC-MS m/z 388.2 (M+H)⁺, 0.87 (ret. time).

Ethyl3-(4-chloro-3-(chloromethyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

Ethyl3-(4-chloro-3-(hydroxymethyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (0.3 g, 0.773 mmol) was dissolved in DCM (2.5 mL). Thionylchloride (0.113 mL, 1.547 mmol) was dispensed and the reaction mixturewas stirred at ambient temperature for 20 minutes. Additional thionylchloride (0.052 mL, 0.712 mmol) was added to the reaction mixture whichwas stirred for an additional 20 minutes. The reaction was concentratedto yield crude ethyl3-(4-chloro-3-(chloromethyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate) (0.3545 g, 113% yield) which was used in the next stepwithout further purification. LC-MS m/z 406.2 (M+H)+, 1.12 (ret. time).

Ethyl3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-chlorophenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

3-(1H-Pyrazol-1-yl) piperidine, hydrochloride (0.02 g, 0.106 mmol) wasdissolved in acetonitrile (2 mL). To this mixture was added DIEA (0.060mL, 0.345 mmol), followed by ethyl3-(4-chloro-3-(chloromethyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(0.035 g, 0.086 mmol). The resulting reaction mixture was heated on amicrowave at 90° C. (high absorption) for 30 min. Additional3-(1H-pyrazol-1-yl)piperidine, hydrochloride (0.005 g, 0.026 mmol) wasadded and the reaction was heated in a microwave at 80° C. (highabsorption) for 30 min. The reaction mixture was concentrated to yieldcrude ethyl 3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-chlorophenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(0.0861 g, 192% yield) which was used in the next step without furtherpurification. LC-MS m/z 521.4 (M+H)⁺, 0.75 (ret. time).

3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-chlorophenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt

Ethyl 3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-chlorophenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(0.0861 g, 0.165 mmol) was dissolved in methanol (2 mL). Then 2.5 M NaOH(0.276 mL, 0.689 mmol) was added and the reaction mixture was heated onmicrowave at 80° C. (high absorption) for 20 min. The mixture wasacidified to pH=3 with 1M HCl, then concentrated. The residue wasdissolved in DMSO (1 mL), filtered and purified by reverse phasepreparative HPLC under formic acid conditions (0.1%). This yielded thetitle compound (0.01652 g, 37.5% yield). LC-MS m/z 493.3 (M+H)⁺, 0.65(ret. time).

Example 1613-(4-chloro-3-((3-hydroxypiperidin-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

Ethyl3-(4-chloro-3-((3-hydroxypiperidin-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

Piperidin-3-ol (0.025 g, 0.246 mmol) was dissolved in acetonitrile (2mL). To this mixture was added was added DIEA (0.086 mL, 0.492 mmol).Then, ethyl3-(4-chloro-3-(chloromethyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(0.05 g, 0.123 mmol) was added. The resulting reaction mixture washeated via microwave at 80° C. (high absorption) for 1 h. The mixturewas concentrated to yield crude ethyl3-(4-chloro-3-((3-hydroxypiperidin-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(0.0898 g, 155% yield) which was used in the next step without furtherpurification. LC-MS m/z 471.5 (M+H)⁺, 0.67 (ret. time).

3-(4-chloro-3-((3-hydroxypiperidin-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

Ethyl3-(4-chloro-3-((3-hydroxypiperidin-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(0.0898 g, 0.184 mmol) was dissolved in methanol (2 mL). Then, 2.5 MNaOH (0.394 mL, 0.984 mmol) was added and the reaction mixutre washeated via microwave at 80° C. (high absorption) for 20 min. The mixturewas acidified to pH=3 with 1 M HCl, then concentrated. The residue wasdissolved in 1 mL DMSO, filtered, and purified by reverse phasepreparative HPLC under natural conditions to yield the title compound(0.0181 g, 33.2% yield). LC-MS m/z 443.5 (M+H)⁺, 0.58 (ret. time).

Example 1623-(3-((3-(1H-Pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

Tert-butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (1.05 g,5.22 mmol) and triethylamine (0.792 g, 7.83 mmol) in dichloromethane(DCM) (50 mL), methanesulfonyl chloride (0.657 g, 5.74 mmol) was added.The reaction mixture was stirred at 0° C. to 25° C. for 3 h. Then it waswashed with water (3×50 mL) and HCl (1 M), (50 mL), dried over MgSO₄,and concentrated to give the title compound tert-butyl3-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.20 g, 3.87 mmol,74.1% yield) as a yellow oil. LC-MS m/z 302.1 (M+Na)⁺, 1.54 min (Ret.time)

Tert-butyl 3-(1H-pyrazol-1-yl)piperidine-1-carboxylate

To a solution of 1H-pyrazole (0.585 g, 8.59 mmol) inN,N-dimethylformamide (DMF) (10 mL) was added sodium hydride (0.309 g,12.89 mmol) in small portions at 00° C. After it was warmed to ambienttemperature and stirred for 1 h, tert-butyl3-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.20 g, 4.30 mmol) wasadded. The reaction mixture was stirred at 100° C. for 18 h. Then it wasquenched with saturated NH₄Cl, and extracted with EtOAc (3×30 mL). Thecombined organic layer was washed with water (2×30 mL), brine (2×30 mL),dried over MgSO₄ and concentrated. The crude product was purified bysilica gel chromatography (EtOAc:petroleum ether=1:5) to give the titlecompound tert-butyl 3-(1H-pyrazol-1-yl)piperidine-1-carboxylate (222 mg,0.786 mmol, 18.30% yield) as a yellow oil. LCMS m/z 252.2 (M+H)⁺, 1.61min (ret. time)

3-(1H-Pyrazol-1-yl)piperidine hydrochloride

To a solution of tert-butyl 3-(1H-pyrazol-1-yl)piperidine-1-carboxylate(222 mg, 0.883 mmol) in 1,4-dioxane (10 mL) was added hydrogen chloride(292 mg, 8.00 mmol) in 1,4-dioxane (705 mg). The reaction mixture wasstirred at 25° C. under the protection of N₂ for 2 h. The solid wasfiltered to give the title compound 3-(1H-pyrazol-1-yl)piperidinehydrochloride (160 mg, 0.836 mmol, 95% yield) as a white solid.

Methyl3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To a solution of 3-(1H-pyrazol-1-yl)piperidine hydrochloride (100 mg,0.535 mmol) in N,N-dimethylformamide (DMF) (10 mL) was addedN-ethyl-N-isopropylpropan-2-amine (323 mg, 2.501 mmol), followed byaddition of a solution of methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(100 mg, 0.250 mmol) in N,N-dimethylformamide (DMF) (10 mL). Thereaction mixture was stirred at 90° C. for 16 h. Then it was poured insaturated NH₄Cl solution (10 mL), extracted with EtOAc (3×20 mL), washedwith water (2×20 mL), saturated NaCl solution (20 mL), dried over MgSO₄,filtered and concentrated to give the title compound methyl3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(85 mg, 0.149 mmol, 59.4% yield) as a yellow oil which was carried tothe next step without further purification. LCMS m/z 515.2 (M+)⁺, 1.54min (ret. time).

3-(3-((3-(1H-Pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

To a solution of methyl3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(85 mg, 0.165 mmol) in tetrahydrofuran (THF) (3 mL) was added lithiumhydroxide (39.6 mg, 1.652 mmol) in water (1 mL) and ethylene glycol(3.00 mL). The reaction was heated in a microwave at 125° C. (highabsorption) for 4 h. Then the organic solvent was removed. The residuewas purified by reverse-phase HPLC (0.05% NH₄HCO₃/H₂O:CH₃CN=5-95%) togive the title compound3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid (15 mg, 0.029 mmol, 17.60% yield) as a white solid. LC-MS m/z 501.3(M+H), 1.56 min (ret. time).

Example 1633-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoicacid, formic acid salt

Ethyl3-(3-(hydroxymethyl)-4-methylphenyl)-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoate

To a solution of (E)-ethyl5-(1-propyl-1H-1,2,3-triazol-4-yl)pent-2-enoate (300 mg, 1.264 mmol) in1,4-dioxane (3 mL) and water (2 mL) was added triethylamine (0.264 mL,1.896 mmol),(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(314 mg, 1.264 mmol) and chloro(1,5-cyclooctadiene)rhodium(I) dimer(34.9 mg, 0.071 mmol). The reaction was then heated to 75° C. andstirred for 2 h. The reaction was removed from the heat and filteredthrough a pad of celite. The filtrate was then concentrated in vacuo andpurified by reverse phase preparative HPLC to provide the title compoundas a yellow oil. (340 mg, 45.6% yield) LC-MS m/z 360 (M+H)⁺, 0.90 min(ret. time).

3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoicacid, formic acid salt

To a solution of ethyl3-(3-(hydroxymethyl)-4-methylphenyl)-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoate(170 mg, 0.288 mmol) in dichloromethane (DCM) (5 mL) was added thionylchloride (0.042 mL, 0.577 mmol). The resulting mixture was stirred atroom temperature for 1 h. The solvent was then removed by evaporationand the residue was redissolved in N,N-dimethylformamide (DMF) (5 mL).To that solution was added DIEA (0.202 mL, 1.154 mmol) and3-(1H-pyrazol-1-yl)piperidine (65.4 mg, 0.433 mmol). The reactionmixture was heated to 75° C. and stirred for 18 h. To the reactionmixture was added LiOH (34.5 mg, 1.442 mmol) and water (5.00 mL) andheated to 60° C. for 18 h. The reaction mixture was concentrated andacidified with formic acid. The residue was purified by reverse phasepreparative HPLC under acidic conditions to provide the title compoundas a light brown oil. (91.7 mg, 66.3% yield) LC-MS m/z 465 (M+H)⁺, 0.68min (ret. time).

Example 1643-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-chlorophenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt

5-Bromo-7-iodo-1,4-dimethyl-1H-benzo[d][1,2,3]triazole

Sodium periodate (0.378 g, 1.769 mmol) was suspended in a stirredmixture of Acetic Acid (2 mL) with Ac₂O (2.98 mL, 31.5 mmol) cooled to5-10° C. Concentrated H₂SO₄ (1.792 mL, 33.6 mmol) was very slowly addeddropwise. Then 5-bromo-1,4-dimethyl-1H-benzo[d][1,2,3]triazole (1 g,4.42 mmol) was added, and the stirring was continued for 16 h at ambienttemperature. The reaction mixture was poured into ice-water containingthe previously dissolved Na₂SO₃. After 15 minutes, the collectedprecipitate was worked up with EtOAc and Na₂SO₃ solution. The crudeproduct was then purified on a silica cartridge (40 g) with a CombiflashCompanion, eluting at 40 mL/min with a gradient running from 100%hexanes to 80% EtOAc/hexanes over 35 min) to give 286 mg (18.34%) of thetitle compound. LC-MS m/z 351.9, 353.9 (M+H)⁺, 1.03 (ret. time).

5-Bromo-7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazole

To a solution of 5-bromo-7-iodo-1,4-dimethyl-1H-benzo[d][1,2,3]triazole(286 mg, 0.813 mmol) in methanol (5 mL) at ambient temperature,copper(I) iodide (77 mg, 0.406 mmol) and Cs₂CO₃ (530 mg, 1.625 mmol)were added. Then the reaction mixture was stirred at 110° C. for 40minutes. The solvent was evaporated under reduced pressure. The crudeproduct was then purified on a silica cartridge (12 g) with a CombiflashCompanion, eluting at 20 mL/min with a gradient running from 100%hexanes to 80% EtOAc/hexanes over 35 min) to give 68 mg (32.7%) of thetitle compound. LC-MS m/z 256.1, 258.0 (M+H)⁺, 0.91 (ret. time).

(E)-Ethyl3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate

To a solution of5-bromo-7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazole (1000 mg, 3.90mmol) in N,N-dimethylformamide (DMF) (20 mL), ethyl acrylate (2346 mg,23.43 mmol), tri-o-tolylphosphine (357 mg, 1.171 mmol),N-ethyl-N-isopropylpropan-2-amine (2019 mg, 15.62 mmol) andpalladium(II) acetate (131 mg, 0.586 mmol) were added. The reactionmixture was heated in a microwave at 110° C. for 1 h. Water was added toquench the reaction. Ethyl acetate was added, and the layers wereseparated. The aqueous layer was extracted once with ethyl acetate, andthe combined organic layers were washed once with brine. The organiclayer was concentrated. The crude product was then purified on a silicacartridge (40 g) with a Combiflash Companion, eluting at 30 mL/min witha gradient running from 100% Hexanes to 80% EtOAc/Hexanes over 35 min)to give 950 mg (88%) of the title compound. LC-MS m/z 276.0 (M+H)⁺, 0.97(ret. time).

Methyl3-(4-chloro-3-(hydroxymethyl)phenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of (E)-methyl3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (261mg, 1 mmol) in 1,4-dioxane (6 mL) and water (2 ml) was added(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(403 mg, 1.500 mmol), triethylamine (0.558 mL, 4.00 mmol) and[Rh(cod)Cl]₂ (24.65 mg, 0.050 mmol). The resulting reaction mixture wasstirred at 90° C. and ambient temperature for 16 h. The solvent wasremoved under reduced pressure and the crude product purified via flashchromatography to afford product methyl3-(4-chloro-3-(hydroxymethyl)phenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(119.9 mg, 0.297 mmol, 29.7% yield). LC-MS m/z 404.3 (M+H)⁺, 0.88 min(ret. time).3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-chlorophenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt

To a solution of methyl3-(4-chloro-3-(hydroxymethyl)phenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(60.6 mg, 0.15 mmol) in dichloromethane (0.50 mL) was added SOCl₂ (0.022mL, 0.300 mmol). The resulting reaction mixture was stirred at ambienttemperature for 15 min and the solvent removed under reduced pressure.The residue was dissolved in acetonitrile (1.5 mL) followed by additionof 3-(1H-pyrazol-1-yl)piperidine (34.0 mg, 0.225 mmol), sodium iodide(11.24 mg, 0.075 mmol) and K₂CO₃ (41.5 mg, 0.300 mmol). The resultingreaction mixture was heated at 40° C. for 21 h and then was filtered.The filter cake was washed with MeCN (2 mL). The combined filtrate wasevaporated down under vacuum then was dissolved in methanol (1.5 mL)before adding NaOH (3 N) (0.250 mL, 0.750 mmol). The resulting reactionmixture was heated with microwave at 80° C. for 20 min and then wasacidified with HCl (3 N) to pH 4-5, evaporated down under vacuum andpurified by reverse phase HPLC to afford product3-(3-((3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-chlorophenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid, formic acid salt (53.1 mg, 0.094 mmol, 62.9% yield). LC-MS m/z523.3 (M+H)⁺, 0.76 min (ret. time).

Example 165(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((7-methoxy-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, 0.5 Formic acid salt

To the mixture of7-methoxy-2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine,hydrochloride (0.133 g, 0.544 mmol) in methanol (4 mL) was added K₂CO₃(0.075 g, 0.544 mmol). The resulting reaction mixture was stirred atambient temperature for 17 h then filtered and concentrated thenfiltered added acetonitrile (4 mL) and filtered to afford intermediatesolution.

To the mixture of (S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(0.100 g, 0.272 mmol) in dichloromethane (1 mL) was added SOCl₂ (0.040mL, 0.544 mmol). The resulting reaction mixture was stirred at ambienttemperature for 20 min and then concentrated then filtered added theabove intermediate solution and DIEA (0.190 mL, 1.089 mmol). Theresulting reaction mixture was heated via microwave at 100° C. for 1 h.The reaction mixture was concentrated and the residue dissolved inmethanol (4 mL). NaOH (3.0 N) (0.726 mL, 2.177 mmol) was added. Theresulting reaction mixture was heated via microwave at 80° C. for 20 minand then neutralized with HCl (2 N) to pH 6 then concentrated andpurified reverse phase HPLC (formic acid modifier) to afford the titlecompound (69.5 mg, 0.126 mmol, 46.3% yield). LC/MS: m/z 529.2 (M+H)⁺,0.86 min (ret. time).

The compounds in Table 17 were prepared by a method similar to the onedescribed for the preparation of(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((7-methoxy-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid. As is appreciated by those skilled in the art, these analogousexamples may involve variations in general reaction conditions.

TABLE 17 Ex LCMS Retention # Structure Name [M + H]⁺ Time (min) 166

(R)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-((7-methoxy-2,2- dimethyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) methyl)-4-methylphenyl) propanoic acid 529.2 0.86 167

(R)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-((8-methoxy-2,2- dimethyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) methyl)-4-methylphenyl) propanoic acid 529.2 0.87 168

(S)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3[triazol-5-yl)-3-(3-((8-methoxy-2,2- dimethyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) methyl)-4-methylphenyl) propanoic acid 529.3 0.87 169

(R)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3[triazol-5-yl)-3-(3-((2,2-dimethyl- 2,3-dihydropyrido[2,3- f][1,4]oxazepin-4(5H)-yl)methyl)-4- methylphenyl)propanoic acid, 0.5 Formic acid salt 500.40.86 170

(S)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl- 2,3-dihydropyrido[2,3- f[1,4]oxazepin-4(5H)-yl)methyl)-4- methylphenyl)propanoic acid, 0.5 Formic acid salt 500.40.85

Example 171rel-(R)-3-(3-((7-Cyano-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

To the mixture of2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carbonitrile,hydrochloride (107 mg, 0.450 mmol) in methanol (5 mL) was added K₂CO₃(83 mg, 0.600 mmol). The resulting reaction mixture was stirred atambient temperature for 30 min then concentrated. The resulting residuewas taken into acetonitrile (4 mL) and tetrahydrofuran (1 mL) andstirred at ambient temperature for 10 min, and filtered to afford theintermediate solution.

To the mixture of ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(110 mg, 0.3 mmol) in dichloromethane (1.5 mL) was added SOCl₂ (0.044mL, 0.600 mmol). The resulting reaction mixture was stirred at ambienttemperature for 10 min then concentrated and then was added the aboveintermediate solution and DIEA (0.210 mL, 1.200 mmol). The resultingreaction mixture was heated via microwave at 100° C. for 1 h then addedmore DIEA (0.105 mL, 0.600 mmol) then heated via microwave at 100° C.for 1 h. The reaction mixture was concentrated then dissolved inmethanol (5 mL) then NaOH (3 N) (0.800 mL, 2.400 mmol) was added. Theresulting reaction mixture was heated via microwave at 60° C. for 20min. The reaction mixture was acidified with HCl (3 N) to pH 4-5,concentrated, purified with reverse phase HPLC (formic acid modifier)then with chiral SFC (Column: Chiralpak AD 20×250 mm, 5 u; Co-solvent:25% EtOH; Flowrate: 50 g/min; Back presure: 100 Bar) to afford the titlecompound (31.8 mg, 0.061 mmol, 20.24% yield). LC/MS: m/z 524.5 (M+H)⁺,0.90 min (ret. time).

The compounds in Table 18 were prepared by a method similar to the onedescribed for the preparation ofrel-(R)-3-(3-((7-cyano-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid. As is appreciated by those skilled in the art, these analogousexamples may involve variations in general reaction conditions.

TABLE 18 Ex LCMS Retention # Structure Name [M + H]⁺ Time (min) 172

rel-(S)-3-(3-((7-Cyano- 2,2-dimethyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) methyl)-4- methylphenyl)-3-(1,4- dimethyl-1H-benzo[d][1,2,3]triazol-5- yl)propanoic acid 524.6 0.90 173

rel-(R)-3-(3-((8-Cyano- 2,2-dimethyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) methyl)-4- methylphenyl)-3-(1,4- dimethyl-1H-benzo[d][1,2,3]triazol-5- yl)propanoic acid 524.6 0.92 174

rel-(S)-3-(3-((8-Cyano- 2,2-dimethyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4- methylphenyl)-3-(1,4- dimethyl-1H-benzo[d][1,2,3]triazol-5- yl)propanoic acid 524.5 0.92

Example 175(R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,7-trimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid

To the mixture of2,2,7-trimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine, hydrochloride(0.044 g, 0.194 mmol) in acetonitrile (2.59 ml) was added DIEA (0.181ml, 1.037 mmol) and (R)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(0.05 g, 0.130 mmol). The resulting reaction mixture was stirred atambient temperature for 12 h then heated via microwave at 80° C. for 60min. The reaction mixture was concentrated then dissolved in methanol (3mL) and NaOH (6 M) (0.166 ml, 1.037 mmol) was added. The resultingreaction mixture was heated via microwave at 90° C. for 30 min andacidified to pH 4-5 with HCl (1 N) then concentrated and purified withreverse phase HPLC (neutral) to give the title compound (20.2 mg, 0.039mmol, 30.4% yield). LC/MS: m/z 513.5 (M+H)+, 0.94 min (ret. time).

The compounds in Table 19 were prepared by a method similar to the onedescribed for the preparation of(R)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,7-trimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid. As is appreciated by those skilled in the art, these analogousexamples may involve variations in general reaction conditions.

TABLE 19 Ex LCMS Retention # Structure Name [M + H]⁺ Time (min) 176

(S)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,7- trimethyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)- yl)methyl)phenyl) propanoic acid 513.5 0.95 177

(R)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-((9-fluoro-2,2- dimethyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) methyl)-4- methylphenyl) propanoic acid 517.4 0.93178

(S)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-((9-fluoro-2,2- dimethyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) methyl)-4- methylphenyl) propanoic acid 517.4 0.94179

(R)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,8- trimethyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)- yl)methyl)phenyl) propanoic acid 513.5 0.94 180

(S)-3-(1,4-Dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,8- trimethyl-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)- yl)methyl)phenyl) propanoic acid 513.5 0.94

Example 181rel-(R)-3-(3-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

3-(3-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

To a suspension of (E)-benzyl3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (500 mg,1.537 mmol),(R)-2-ethyl-4-(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(657 mg, 1.614 mmol), and [RhCl(cod)]₂ (76 mg, 0.154 mmol) in1,4-dioxane (8 mL) and water (2 mL) at ambient temperature was addedtriethylamine (0.643 mL, 4.61 mmol). The resulting suspension was heatedat 90° C. for 1 h. The reaction mixture was passed through celite andwashed with EtOAc. The organic layer was collected and concentrated togive the crude product. It was purified by silica gel chromatography.This intermediate was redissolved in MeOH (8 mL). LiOH (221 mg, 9.22mmol) was added and heated at 60° C. for 1.5 h. Solvent was removed. 6 NHCl was added until pH˜1. 1 mL of DMSO was added. The reaction mixturewas concentrated and then purified with preparative HPLC under acidicconditions (using 0.1% TFA as modifier) to give the title compound (400mg, 0.774 mmol, 50.4% yield). LC/MS: m/z 517.4 (M+H)⁺, 0.86 min (ret.time).

Methylrel-(R)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To the mixture of3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (400 mg, 0.774 mmol) in methanol (8 mL) was added H₂SO₄ (conc.)(0.413 mL, 7.74 mmol). The resulting reaction mixture was stirred atambient temperature for 23 h then quenched with Na₂CO₃ (615 mg, 5.81mmol), diluted with EtOAc (20 mL), and filtered. The filtrate was driedover Na₂SO₄, filtered, concentrated then purified with chiral SFC(Column: Chiralpak IA 20×250 mm, 5 u; Co-solvent: 30% MeOH:IPA 1:1;Flowrate: 50 g/min; Back presure: 100 Bar) to give the title compound(112.4 mg, 0.212 mmol, 27.4% yield). LC/MS: m/z 531.3 (M+H)⁺, 1.01 min(ret. time).

rel-(R)-3-(3-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

To the solution of methylrel-(R)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(110 mg, 0.207 mmol) in methanol (2 mL) was added NaOH (3.0 N) (0.345mL, 1.036 mmol). The reaction mixture was heated via microwave at 80° C.for 20 min then acidified with HCl (3.0 N) (0.345 mL, 1.036 mmol),concentrated, and extracted with DCM (3×3 mL). The combined organiclayer was dried over MgSO₄, filtered, and concentrated to give the titlecompound (106.8 mg, 0.207 mmol, 100% yield). LC/MS: m/z 517.3 (M+H)⁺,0.86 min (ret. time).

The compounds in Table 20 were prepared by a method similar to the onedescribed for the preparation ofrel-(R)-3-(3-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid. As is appreciated by those skilled in the art, these analogousexamples may involve variations in general reaction conditions.

TABLE 20 Ex LCMS Retention # Structure Name [M + H]⁺ Time (min) 182

rel-(S)-3-(3-(((R)-2-Ethyl- 2,3-dihydrobenzo[f][1,4] oxazepin-4(5H)-yl)methyl)-4- methylphenyl)-3-(1-ethyl- 4-fluoro-1H-benzo[d][1,2,3[triazol-5- yl)propanoic acid 517.4 0.86

Example 183(S)-3-(3-(((S)-3-(1H-Pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

(S)-Methyl3-(3-(((S)-3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To the mixture of 3-(1H-pyrazol-1-yl)piperidine, hydrochloride (0.2645g, 1.409 mmol) in acetonitrile (10.38 ml) was added DIEA (1.450 ml, 8.30mmol), and (S)-methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(0.415 g, 1.038 mmol). The resulting reaction mixture was heated viamicrowave at 80° C. for 1 h. The reaction mixture was concentrated thenpurified with reverse phase HPLC (neutral) then further purified withchiral SFC (Column: Chiralpak IA 20×250 mm, 5 u; Co-solvent: 20% IPA;Flowrate: 50 g/min; Back presure: 100 Bar) to give the title compound(0.124 g, 0.241 mmol, 23.22% yield). LC/MS: m/z 515.4 (M+H)⁺, 0.89 min(ret. time).

(S)-3-(3-(((S)-3-(1H-Pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

The mixture of (S)-methyl3-(3-(((S)-3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(0.124 g, 0.241 mmol) in methanol (4.82 ml) and sodium hydroxide (2 N)(0.602 ml, 1.205 mmol) was heated via microwave at 130° C. for 3 h. Tothe reaction mixture was added more sodium hydroxide (2 N) (0.361 ml,0.723 mmol) then heated via microwave at 135° C. for 1 h twice. Thereaction mixture was acidified with HCl (1 N) to pH 4-5 thenconcentrated. The result residue was extracted with ethyl acetate (4×2mL) and was filtered. The combined organic layer was concentrated togive the title compound (88.3 mg, 0.176 mmol, 73.2% yield). LC/MS: m/z501.3 (M+H)⁺, 0.86 min (ret. time).

The compounds in Table 21 were prepared by a method similar to the onedescribed for the preparation of(S)-3-(3-(((S)-3-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid. As is appreciated by those skilled in the art, these analogousexamples may involve variations in general reaction conditions.

TABLE 21 Ex LCMS Retention # Structure Name [M + H]⁺ Time (min) 184

(S)-3-(3-(((R)-3-(1H- Pyrazol-1-yl)piperidin-1- yl)methyl)-4-methylphenyl)-3-(1,4- dimethyl-1H- benzo[d][1,2,3]triazol-5- yl)-2,2-dimethylpropanoic acid 501.3 0.84

Example 1853-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((3-(phenylsulfonyl)piperidin-1-yl)methyl)phenyl)propanoicacid

tert-Butyl 3-(phenylthio)piperidine-1-carboxylate

To the mixture of NaH (0.042 g, 1.038 mmol) in DMF (2.5 mL) undernitrogen was added benzenethiol (0.085 ml, 0.830 mmol). The mixture wasstirred at ambient temperature for 5 min then tert-butyl3-((methylsulfonyl)oxy)piperidine-1-carboxylate (0.29 g, 1.038 mmol) inDMF (2.5 mL) was added. The resulting reaction mixture was stirred atambient temperature for 2 h then heated via microwave at 100° C. for 1h. The reaction mixture was quenched with NH₄Cl (2 mL, saturated) thenconcentrated. The residue was taken up in EtOAc (35 mL) and water (5mL). After removing the aqueous layer, the organic layer was washed withwater (2×10 mL), brine (10 mL) and filtered through an isolute IST (70mL) phase separator. The filtrate was concentrated and purified by flashchromatography to give the title compound (0.1201 g, 0.409 mmol, 39.4%yield). LC/MS: m/z 294.1 (M+H)⁺, 1.30 min (ret. time).

3-(Phenylsulfonyl)piperidine, hydrochloride

To the mixture of tert-butyl 3-(phenylthio)piperidine-1-carboxylate(0.1201 g, 0.409 mmol) in dichloromethane (2.047 ml) was added mCPBA(0.229 g, 1.023 mmol). The resulting reaction mixture was stirred atambient temperature for 30 min then NaOH (1 N) (3 mL) was added followedby DCM (30 mL) and washed with 1 M NaOH (2×5 mL). The organic layer wasfiltered through an isolute IST (70 mL) phase separator. The filtratewas concentrated and the residue dissolved in dichloromethane (2.047 ml)then HCl (4 M in dioxane) (1.023 ml, 4.09 mmol) was added. The resultingreaction mixture was stirred at ambient temperature for 1 h thenevaporated down under vacuum to give the title compound (0.1116 g, 0.426mmol, 104% yield). LC/MS: m/z 226.1 (M+H)⁺, 0.55 min (ret. time).

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((3-(phenylsulfonyl)piperidin-1-yl)methyl)phenyl)propanoicacid

To the mixture of 3-(phenylsulfonyl)piperidine, hydrochloride (0.044 g,0.168 mmol) in acetonitrile (2.59 ml) was added DIEA (0.181 ml, 1.037mmol), and ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(0.05 g, 0.130 mmol). The resulting reaction mixture was heated viamicrowave at 80° C. for 1 h then concentrated. The resulting residue wasdissolved in methanol (2.5 mL) then NaOH (6 N) (0.124 ml, 0.777 mmol)was added. The resulting reaction mixture was heated via microwave at90° C. for 30 min then acidified to pH 4 with HCl (1 N), concentrated,and purified via reverse phase HPLC (neutral) to give the title compound(36.9 mg, 0.067 mmol, 52.1% yield). LC/MS: m/z 547.5 (M+H)⁺, 0.79 min(ret. time).

The compounds in Table 22 were prepared by a method similar to the onedescribed for the preparation of3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((3-(phenylsulfonyl)piperidin-1-yl)methyl)phenyl)propanoicacid. As is appreciated by those skilled in the art, these analogousexamples may involve variations in general reaction conditions.

TABLE 22 Ex LCMS Retention # Structure Name [m + H]⁺ Time (min) 186

3-(3-((3- (Cyclohexylsulfonyl) piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4- dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)propanoic acid 553.5 0.82

Example 1873-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-N-(methylsulfonyl)propanamide

To the mixture of 2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine,hydrochloride (0.055 g, 0.259 mmol) in acetonitrile (2 mL) was addedDIEA (0.362 ml, 2.073 mmol) then ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(0.1 g, 0.259 mmol). The resulting reaction mixture was heated viamicrowave at 100° C. for 1 h then concentrated and purified by flashchromatography to afford intermediate ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoate(0.0833 g, 0.158 mmol, 61.0% yield). This intermediate was dissolved inmethanol then NaOH (6 N) (0.332 ml, 2.073 mmol) added. The resultingreaction mixture was heated via microwave at 80° C. for 1 h thenacidified with HCl (1 N) to pH 4-5 and then concentrated. The residuewas dissolved in EtOAc and DCM (4 mL each) and then filtered. Thefiltrate was concentrated then dissolved in DCM (3 mL) then EDC (0.04 g,0.209 mmol), DMAP (0.022 g, 0.180 mmol) and DIEA (0.068 ml, 0.389 mmol)under nitrogen atmosphere were added. This reaction mixture was stirredfor 15 minutes then methanesulfonamide (0.0283 g, 0.298 mmol) was added.The resulting reaction mixture was stirred at ambient temperature for 48h under nitrogen then HCl (1 N) (2 mL) was added. The organic layer wasseparated and filtered through an isolute IST (70 mL) phase separator.The filtrate was evaporated and purified with reverse phase HPLC(neutral) to give the title compound (16 mg, 0.028 mmol, 10.72% yield).LC/MS: m/z 576.4 (M+H)⁺, 0.84 min (ret. time).

Example 188(S)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

Example 189(R)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

(S)-Methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To a solution of (S)-methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(710 mg, 1.861 mmol) in dichloromethane (10 mL) at ambient temperaturewas added thionyl chloride (0.272 mL, 3.72 mmol). The reaction wasstirred for 40 min. The resulting mixture was concentrated to give thetitle compound (750 mg, 1.875 mmol, 101% yield). LC-MS m/z 400.2 (M+H)⁺,1.21 min (ret. time)

3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

Methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(414 mg, 1 mmol),(R)-2-ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine hydrochloride(215 mg, 1.000 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.699 ml,4.00 mmol) in acetonitrile (2 mL) were heated to 120° C. biotageinitiator microwave (high power) for 1 h. Solvent was then removed undera stream of nitrogen at 50 C. The crude product was redissolved inmethanol (2 mL) and water (1 mL) and lithium hydroxide (479 mg, 20.00mmol) was added. The solution was heated to 130° C. in a biotageinitiator microwave (high power) for 3 hs. DMSO (2 mL) was added to thesolution and the methanol and water removed with a V-10 vortexevaporator. The DMSO solution was then accidified with 1 N HCl to a pHof 2. Water was removed with a V-10 vortex evaporator and the DMSOfiltered and purified on a Gilson HPLC with formic acid modifier to givethe title compound (250 mg, 0.462 mmol, 46.2% yield). LC/MS: m/z 123.4(M+H)⁺, 0.12 min (ret. time)

(S)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid and(R)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid (250 mg, 0.462 mmol) was separated by Chiral SFC (Column: ChiralpakIA 20×250 mm, 5 u; Co-solvent: 20% EtOH; Flowrate: 50 g/min; Backpressure: 100 Bar) to give single enantiomerically pure diastereomer(S)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid (63 mg, 0.116 mmol, 25.2% yield) (chiral SFC ret. time: 4.75 min)and(R)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid (74 mg, 0.137 mmol, 29.6% yield) (chiral SFC ret. time: 6.07 min)LC-MS m/z 542.4 (M+H)⁺, 0.88 min (ret. time). However,(S)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid was not pure enough. The crude product was purified by reversephase preparative HPLC using 0.1% formic acid as a solvent modifier toprovide the title compound(S)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid, formic acid salt (55 mg, 0.094 mmol, 20.28% yield) as solid. LC-MSm/z 542.6 (M+H)⁺, 0.93 min (ret. time)

Example 190(2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid

N-Ethyl-3-fluoro-2-nitroaniline

To a solution of 1,3-difluoro-2-nitrobenzene (10 g, 62.9 mmol) inethanol (300 mL) was added ethanamine (47.2 g, 314 mmol) slowly at 0° C.The reaction mixture was stirred at 0° C. for 0.5 h and then warmed to25° C. for another 4 h. After removing the solvent, the residue waspurified via silica gel chromatography (80 g, PE/EA=5%) to give thetitle compound (8.0 g, 43.4 mmol, 69.1% yield) as a solid. LC/MS: m/z185 (M+H)⁺, 1.70 min (ret. time)

4-Bromo-N-ethyl-3-fluoro-2-nitroaniline

To a solution of N-ethyl-3-fluoro-2-nitroaniline (8.0 g, 43.4 mmol) inDMF (100 mL) at 0° C. was added a solution of N-bromosuccinimide (6.19g, 34.8 mmol) dropwise. The mixture was stirred at 0° C. for 6 h. Themixture was quenched with water (500 mL) and extracted with ethylacetate (3×400 mL). The combined organic layer was washed with water(2×100 mL), brine (2×100 mL), dried (Na₂SO₄) and concentrated. Theresidue was purified by silica gel chromatography (PE/EA=12%) to givethe title compound (8.2 g, 31.2 mmol, 71.8% yield) as yellow oil. LCMS:m/z 263 (M+H)⁺1.80 min (ret. time)

4-Bromo-N1-ethyl-3-fluorobenzene-1,2-diamine

To a solution of 4-bromo-N-ethyl-3-fluoro-2-nitroaniline (8000 mg, 30.4mmol) in ethanol (100 mL) and 1,2-dichloroethane (DCE) (100 mL) undernitrogen at 0° C. was added Raney nickel (1983 mg, 30.4 mmol, 90% inwater) slowly. Hydrazine hydrate (2.237 mL, 45.6 mmol) was addeddropwise. The reaction mixture was stirred at 0° C. for 1 h, filtered,and concentrated. The residue was purified by silica gel chromatography(hexane:ethyl acetate=4:1) to give the title compound (6500 mg, 27.9mmol, 92% yield). LC-MS m/z 233.0 (M+H)⁺1.90 (ret. time)

5-Bromo-1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazole

A stirred suspension of 4-bromo-N1-ethyl-3-fluorobenzene-1,2-diamine(6.5 g, 27.9 mmol) and sulfuric acid (5.95 mL, 112 mmol) in water (300mL) at 0° C. was treated with a solution of sodium nitrite (2.89 g, 41.8mmol) in water (50 mL). The mixture was stirred at 0° C. for 2 h. Themixture at 0° C. was basified to pH 8 using 2 N NaOH and extracted withDCM (3×200 mL). The combined organics were washed with water (2×80 mL),brine (2×80 mL), dried (Na₂SO₄) and concentrated. The residue waspurified by silica gel chromatography (120 g, PE/EA=60%) to give thetitle compound (5.2 g, 21.31 mmol, 76% yield) as a colorless oil. LCMS:m/z 243.9 (M+H)⁺1.63 min (ret. time)

(E)-Benzyl 3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)acrylate

A mixture of 5-bromo-1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazole (5.2 g,21.31 mmol), benzyl acrylate (6.91 g, 42.6 mmol), diacetoxypalladium(0.239 g, 1.065 mmol), tri-otolylphosphine (0.648 g, 2.131 mmol) andtriethylamine (14.85 ml, 107 mmol) was heated to 120° C. for 6 h underN₂. The reaction mixture was quenched with 200 mL ethyl acetate, andthen washed with water (3×100 mL). The organics were dried over Na₂SO₄and the The solvent was removed. The residue was purified by silica gelchromatography (120 g, eluted with PE:EA=2:1-1:1) to give the titlecompound (2.7 g, 8.30 mmol, 39.0% yield) as a solid. LCMS m/z 326.3(M+H)⁺, 2.02 min (ret. time)

Benzyl3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

To a solution of (E)-benzyl3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (2.7 g, 8.30mmol) in dioxane (40 mL) and water (20 mL) was added(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(6.18 g, 24.90 mmol) and TEA (3.47 mL, 24.90 mmol). The reaction wasstirred for 5 min, then chloro(1,5-cyclooctadiene)rhodium(I) dimer(0.205 g, 0.415 mmol) was added under nitrogen. The reaction mixture wasstirred at 90° C. for 16 h. The The solvent was removed and the residuewas purified by silica gel chromatography (PE:EtOAc=6:1) to give titlecompound (2.0 g, 4.47 mmol, 53.9% yield) as a yellow oil. LC-MS m/z448.1 (M+18)⁺, 2.10(ret. time)

(S)-Benzyl3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoateand (R)-benzyl3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

Benzyl3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(2 g, 4.47 mmol) was separated by Chiral SFC (Column: AS-H 20*250 mm, 5um; Co-solvent: CO₂/MeOH (0.1 DEA)=85/15; Flowrate: 80 g/min; Backpressure: 100 Bar) to give single enantiomerically pure (S)-benzyl3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(0.9 g, 2.011 mmol, 45%) (chiral SFC ret. time: 2.4 min). LCMS m/z 448.1(M+H)⁺, 1.69 (ret. time) and

(R)-benzyl3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(0.8 g, 1.788 mmol, 40%) (chiral SFC ret. time: 5.43 min) LCMS m/z 448.1(M+H)⁺, 1.69 (ret. time)

(S)-benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of (S)-benzyl3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(4000 mg, 8.94 mmol) in dichloromethane (50 mL) at ice bath were addedimidazole (669 mg, 9.83 mmol) and tert-butylchlorodimethylsilane (1617mg, 10.73 mmol). The reaction mixture was stirred at 10° C. for 2 h. Themixture was quenched with water (10 mL) and extracted with DCM (3×20mL). The combined organic layer was washed with water (2×10 mL) andbrine (2×8 mL), dried (Na₂SO₄), filtered and concentrated. The crudeproduct was purified by silica gel chromatography (80 g, PE:EA=3:1) togive the title compound (4100 mg, 6.93 mmol, 78% yield) as a solid. LCMSm/z 562.1 (M+H)⁺, 2.12 (ret. time)

(R)-4-benzyl-3-((S)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoyl)oxazolidin-2-one

(S)-Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(640 mg, 1.139 mmol) and Et₃N (0.476 mL, 3.42 mmol) in ethyl acetate (20mL) was passed through a 10% Pd—C cartridge at 1 mL/minute on an H-cubeflow hydrogenation instrument set on full H₂. After 40 min, the solventwas removed and the residue dissolved in tetrahydrofuran (10.00 mL).Di(1H-imidazol-1-yl)methanone (CDl) (277 mg, 1.709 mmol) was added andthe reaction stirred for 16 h. Consumption of the starting material wasmonitored by TLC. The solution was then diluted with ethyl acetate (10mL) and washed with brine (2 mL) and dried (sodium sulfate). Thesolution was concentrated in vacuo and dissolved in acetonitrile (10mL). 2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepine (0.034 mL, 0.228mmol) and (R)-4-benzyloxazolidin-2-one (222 mg, 1.253 mmol) were addedand the solution stirred at ambient temperature for 16 h. The reactionwas quenched with water, concentrated, then extracted with ethyl acetate(3×). The combined organic fractions were washed (brine) andconcentrated. The crude product was purified by silica gelchromatography (Combiflash) (product came out at 30% ethyl acetate inhexane). Desired fractions were concentrated to give the title compound(509 mg, 0.807 mmol, 70.8% yield). LC/MS: m/z 631.5 (M+H)⁺, 1.64 min(ret. time)

(R)-4-Benzyl-3-((2R,3S)-3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one

To a mixture of(R)-4-benzyl-3-((2R,3S)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one(400 mg, 0.620 mmol) in dichloromethane (2 mL) was added thionylchloride (0.091 mL, 1.241 mmol). The reaction was stirred at ambienttemperature for 7 h. The resulting mixture was concentrated to give thetitle compound (393 mg, 0.716 mmol, 115% yield) as a solid. LC/MS: m/z549.4 (M+H)⁺, 1.37 min (ret. time)

(R)-4-Benzyl-3-((2R,3S)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one

To a mixture of(R)-4-benzyl-3-((2R,3S)-3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one(100 mg, 0.182 mmol) in acetonitrile (3 mL) was added2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride (78mg, 0.364 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.095 mL, 0.546mmol). The reaction was heated via microwave reactor at 120° C. for 1 h.The solvent was removed. The crude product was purified by silica gelchromatography to give the title compound (107 mg, 0.155 mmol, 85%yield). LC/MS: m/z 691.6 (M+H)⁺, 1.17 min (ret. time)

(2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid

To a mixture of(R)-4-benzyl-3-((2R,3S)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one(107 mg, 0.155 mmol) in tetrahydrofuran (2 mL) and water (0.5 mL)THF/water (4:1) was added hydrogen peroxide (0.127 mL, 1.239 mmol) and 2M lithium hydroxide (0.232 mL, 0.465 mmol). The reaction was stirred for2 h. The reaction was quenched with saturated aqueous ammonium chloride(5 mL) and extracted with ethyl acetate twice. The combined organiclayer was concentrated then purified with preparative HPLC under acidicconditions (with 0.1% TFA as modifier). Product fractions were combinedand concentrated and re-dissolved in ethyl acetate (10 mL), and washedwith saturated NaHCO₃ twice. The organic layer was dried over sodiumsulfate, filtered and concentrated to give the title compound (42 mg,0.079 mmol, 51.0% yield). LC/MS: m/z 532.4 (M+H)⁺, 0.90 min (ret. time)

The compounds in Table 23 were prepared by a method similar to the onedescribed for the preparation of(2R,3S)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid. As is appreciated by those skilled in the art, these analogousexamples may involve variations in general reaction conditions.

TABLE 23 LCMS Retention Ex # Structure Name [m + H]⁺ Time (min) Example191

(2R,3S)-3-(3-(((R)-2- Ethyl-2,3- dihydropyrido[2,3-f][1,4]oxazepin-4(5H)- yl)methyl)-4- methylphenyl)-3-(1-ethyl-4-fluoro-1H- benzo[d][1,2,3]triazol-5- yl)-2-methylpropanoic acid532.4 0.87 Example 192

(2R,3S)-3-(1-Ethyl-4- fluoro-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9- fluoro-2,3- dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)- 4-methylphenyl)-2- methylpropanoic acid 549.40.94 Example 193

(2R,3S)-3-(3-((2,2- Dimethyl-2,3-dihydro- benzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4- methylphenyl)-3-(1- ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5- yl)-2-methylpropanoic acid, Sodium salt 531.50.93 Example 194

(2R,3S)-3-(4-Chloro-1- ethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl- 2,3-dihydropyrido[3,2- f][1,4]oxazepin-4(5H)-yl)methyl)-4- methylphenyl)-2- methylpropanoic acid 548.3 0.86 Example195

(2R,3S)-3-(3-((2,2- Dimethyl-2,3- dihydropyrido[3,2-f][1,4]oxazepin-4(5H)- yl)methyl)-4- methylphenyl)-3-(1-ethyl-4-fluoro-1H- benzo[d][1,2,3]triazol-5- yl)-2-methylpropanoic acid532.3 0.83 Example 196

(2R,3S)-3-(3-((2,2- Dimethyl-2,3- dihydropyrido[3,4-f][1,4]oxazepin-4(5H)- yl)methyl)-4- methylphenyl)-3-(1-ethyl-4-methyl-1H- benzo[d][1,2,3]triazol-5- yl)-2-methylpropanoic acid,Trifluoroacetic acid salt 528.4 0.94

Example 197(2S,3R)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate,Sodium salt

(R)-Ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of (R)-ethyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(5 g, 13.11 mmol) in dichloromethane (100 mL) were added imidazole(0.892 g, 13.11 mmol) and tert-butylchlorodimethylsilane (2.173 g, 14.42mmol). The reaction mixture was stirred at 0° C. to 25° C. for 2 h. Themixture was quenched with water (100 mL) and extracted with DCM (3×150mL). The combined organic layer was washed with brine (200 mL), dried(Na₂SO₄), filtered and concentrated. The residue was purified withsilica gel chromatography (PE:EA=5:1) to give (5.2 g, 9.44 mmol, 72.0%yield) as yellow oil. LC-MS m/z 496.3 (M+H)⁺, 2.39 (ret. time)

(R)-3-(3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

To a solution of (R)-ethyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(5.2 g, 10.49 mmol) in tetrahydrofuran (10 mL)/methanol (5 mL) was addedLiOH (0.462 g, 19.31 mmol) in water (8 mL). The reaction mixture wasstirred at 25° C. for 4 h. The organic solvent was removed. The residuewas adjusted to pH 5 with HCl (3 M, 5 mL) and extracted with ethylacetate (2×100 mL). The organic layer was washed with water (50 mL),dried over sodium sulfate, filtered and concentrated to give the titlecompound (4.8 g, 6.26 mmol, 59.7% yield) as yellow oil. LC-MS m/z 468.3(M+H)+, 1.73 (ret. time)

(R)-Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of(R)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (4.8 g, 10.26 mmol) in acetonitrile (30 mL) was added(bromomethyl)benzene (1.931 g, 11.29 mmol) and K₂CO₃ (2.84 g, 20.53mmol). The solution was stirred at 25° C. for 4 h. The residue waspurified by silica gel chromatography (PE:EtOAc=10:1) to give the titlecompound (4 g, 5.59 mmol, 54.5% yield) as a yellow oil. LC-MS m/z 558.3(M+H)⁺, 2.54 (ret. time)

(2S,3R)-Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate

Batch 1: To a solution of (R)-benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(500 mg, 0.896 mmol) in tetrahydrofuran (10 mL) was added LDA (1.569 mL,3.14 mmol) at −78° C. The reaction was stirred for 45 min and MeI (0.112mL, 1.793 mmol) was added at −78° C. The red wine color turned to lightyellow. The reaction was stirred for 45 min. The residue was dilutedwith EtOAc (75 mL) and water (25 mL). The aqueous layer was extractedagain with EtOAc (25 mL) and the combined EtOAc was washed withsaturated NaCl (25 mL), dried (Na₂SO₄) and concentrated. Batch 2 to 8was the same procedure as batch 1. Eight batches were combined. Theresidue was purified by reverse phase preparative HPLC using 0.05% TFAas a solvent modifier to give the title compound (contained 55% of titlecompound and 38% (2S,3R)-benzyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate)as a yellow oil. LC-MS m/z 571.8 (M+H)⁺, 2.32 (ret. time)

(3R)-Benzyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate

To a solution of (3R)-benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate(1.1 g, 1.924 mmol) in tetrahydrofuran (20 mL) at 0° C., TBAF (0.604 g,2.308 mmol) was added. The reaction mixture was stirred at 0° C. for 1h. The mixture was quenched with saturated NH₄Cl solution (20 mL) andextracted with ethyl acetate (3×100 mL). The organic layer was washedwith brine (100 mL), dried (Na₂SO₄) and concentrated. The residue waspurified by silica gel chromatography (PE:EtOAc=1:1) to give the titlecompound (740 mg, 1.503 mmol, 78% yield) as a colorless oil. LC-MS m/z457.9 (M+H)⁺, 1.75 (ret. time)

(3R)-Benzyl3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate

To a solution of (3R)-benzyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(200 mg, 0.437 mmol) in dichloromethane (3 mL) was added thionylchloride (0.064 mL, 0.874 mmol). The mixture was stirred for 40 min. Theresulting mixture was concentrated to give (2S,3R)-benzyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate.This was re-dissolved in acetonitrile (3 mL).(R)-2-ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine hydrochloride(113 mg, 0.525 mmol) was added. The mixture was heated via microwave at120° C. for 1 h. The resulting mixture was concentrated. The crudeproduct was purified by silica gel chromatography (Combiflash) (productcame out at 50% ethyl acetate in hexane). Desired fractions wereconcentrated to give the title compound (101 mg, 0.163 mmol, 37.4%yield) LC-MS m/z 618.6 (M+H)⁺, 1.02 min (ret. time)

(2S,3R)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid

A solution of (3R)-benzyl3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate(100 mg, 0.162 mmol) in ethyl acetate (5 mL) was passed through anH-Cube (1 mL/min, 25° C., Pd/C cartridge, 1 bar) for 3 h. The resultingmixture was concentrated and purified by reverse phase preparative HPLCusing 0.1% TFA as a solvent modifier to provide the title compound (88mg, 0.073 mmol, 44.9%). LC-MS m/z 528.3 (M+H)⁺, 0.80 min (ret. time)

(2S,3R)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate,Sodium salt

48.5 mg of(2S,3R)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid (6:1 TFA vs. parent) was dissolved in ethyl acetate (8 mL) andwashed with saturated NaHCO₃. The aqueous layer was washed with ethylacetate again. The combined organic layer was dried over sodium sulfate,filtered and concentrated to give the title compound (23 mg, 0.042 mmol,45.5% yield) as solid. LC-MS m/z 528.3 (M+H)⁺, 0.80 min (ret. time) Thecompounds in Table 24 were prepared by a method similar to the onedescribed for the preparation of(2S,3R)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid. As is appreciated by those skilled in the art, these analogousexamples may involve variations in general reaction conditions.

TABLE 24 LCMS Retention Ex # Structure Name [m + H]⁺ Time (min) Example198

(2S,3R)-3-(1,4- Dimethyl-1H- benzo[d][1,2,3]triazol- 5-yl)-3-(3-((2,2-dimethyl-2,3- dihydropyrido[3,4- f][1,4]oxazepin-4(5H)- yl)methyl)-4-methylphenyl)-2- methylpropanoic acid, 0.1 formic acid salt 514.5 0.93Example 199

(2S,3R)-3-(3-(((R)-2- Ethyl-2,3- dihydrobenzo[f][1,4] oxazepin-4(5H)-yl)methyl)-4- methylphenyl)-3-(1- ethyl-4-methyl-1H-benzo[d][1,2,3]triazol- 5-yl)-2- methylpropanoic acid 527.1 0.90

Example 200(2S,3R)-3-(3-((2,2-Dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid, 2 Trifluoroacetic acid salt

(R)-3-(3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

(R)-Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(200 mg, 0.359 mmol) in methanol (17.928 mL) was passed through anH-cube flow reactor with a 10% Pd—C cartridge for 1.5 h at 1 mL/min onfull H2 mode. The methanol was then removed. The crude material waspurified by silica gel chromatography using 0-10% MeOH/DCM to give thetitle compound (138 mg, 0.295 mmol, 82% yield). LC/MS: m/z 468.2 (M+H)⁺,1.41 min (ret. time)

(S)-4-Benzyl-3-((R)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoyl)oxazolidin-2-one

CDl (71.8 mg, 0.443 mmol) was added to a solution of(R)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (138 mg, 0.295 mmol) in tetrahydrofuran (2.95 mL) at ambienttemperature and the reaction stirred for 16 hs. Consumption of thestarting material was monitored by TLC. The solution was then dilutedwith DCM (10 mL) and washed with water (2 mL) and dried (sodiumsulfate). The solution was concentrated and dissolved in acetonitrile(2.95 mL). (S)-4-benzyloxazolidin-2-one (57.5 mg, 0.325 mmol) and DBU(8.90 μL, 0.059 mmol) were added and the solution stirred at ambienttemperature for 16 hs. The reaction was quenched with saturated aqueousammonium chloride and extracted with ethyl acetate (3×). The combinedorganic fractions were washed (brine), dried (sodium sulfate) andsolvent removed in vacuo. The product was purified by silica gelchromatography (EtOAc/hexanes 0-100%) to give the title compound (767mg, 1.224 mmol, 84% yield). LC/MS: m/z 627.2 (M+H)⁺, 1.59 min (ret.time)

(S)-4-Benzyl-3-((2S,3R)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one

Sodium bis(trimethylsilyl)amide (1.346 mL, 1.346 mmol) was addeddropwise to a solution of(S)-4-benzyl-3-((R)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoyl)oxazolidin-2-one(767 mg, 1.224 mmol) in tetrahydrofuran (12.236 mL) at −78° C. and thereaction stirred for 60 minutes. Methyl iodide (3.06 mL, 6.12 mmol) wasthen added and the solution stirred for 1 h at −78° C. and then warmedto ambient temperature. The reaction was quenched with saturated aqueousammonium chloride and extracted with ethyl acetate (3×). The combinedorganic fractions were washed (brine), dried (sodium sulfate) andsolvent removed in vacuo. The product was purified by silica gelchromatography (EtOAc/hexanes 0-100%) to give the title compound (591mg, 0.922 mmol, 75% yield). LC/MS: m/z 641.2 (M+H)⁺, 1.68 min (ret.time)

(S)-4-Benzyl-3-((2S,3R)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoyl)oxazolidin-2-one

TBAF (2.029 mL, 2.029 mmol) was added dropwise to a solution of(S)-4-benzyl-3-((2S,3R)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one(591 mg, 0.922 mmol) in tetrahydrofuran (18.856 mL) at 0° C. and thereaction stirred for 30 minutes. The desired product was purified bysilica gel chromatography to give the title compound (157 mg, 0.298mmol, 32.3% yield). LC/MS: m/z 527.6 (M+H)⁺, 1.16 min (ret. time)

(S)-4-Benzyl-3-((2S,3R)-3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one

Thionyl chloride (0.022 mL, 0.298 mmol) was added to a solution of(S)-4-benzyl-3-((2S,3R)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoyl)oxazolidin-2-one(157 mg, 0.298 mmol) in dichloromethane (2.379 mL) at ambienttemperature. The solution was stirred for 30 minutes then concentrated.The excess thionyl chloride was removed under reduced pressure utilizinga V-10 vortex evaporator to give the title compound (162 mg, 0.298 mmol,100% yield). The product was taken to the next step without furtherpurification. LC/MS: m/z 545.3 (M+H)⁺, 1.39 min (ret. time)

(2S,3R)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid, 2 Trifluoroacetic acid salt

(S)-4-Benzyl-3-((2S,3R)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoyl)oxazolidin-2-one(70 mg, 0.133 mmol),2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride(56.8 mg, 0.266 mmol), and N-ethyl-N-isopropylpropan-2-amine (69.6 μl,0.399 mmol) in acetonitrile (1.2 mL) were heated in a biotage microwavereactor (high power) at 120° C. for 2.5 hs. The solvent was removed andand the crude product was dissolved in THF/Water (4:1). hydrogenperoxide (0.109 mL, 1.063 mmol) and lithium hydroxide (9.55 mg, 0.399mmol) were added and the solution stirred for 16 hs. The reaction wasquenched with saturated aqueous ammonium chloride (5 mL) and extractedwith ethyl acetate (5×20 mL). The combined organic fractions wereevaportated and dissolved in DMSO. The residue was purified by reversephase preparative HPLC using 0.1% TFA as a solvent modifier to providethe title compound (50 mg, 0.066 mmol, 49.8% yield). LC/MS: m/z 527.4(M+H)+, 0.92 min (ret. time)

Example 201(2S,3R)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methyl-3-(4-methyl-3-((2-(piperidin-1-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoicacid

Benzyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate

To a solution of (3R)-benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate(600 mg, 1.049 mmol) in tetrahydrofuran (10 mL) at 0° C. was added TBAF(329 mg, 1.259 mmol). The reaction mixture was stirred at 0° C. for 1 h.The mixture was quenched with saturated NH₄Cl solution (20 mL) andextracted with ethyl acetate (3×100 mL). The organic layer was washedwith brine (100 mL), dried (Na₂SO₄) and concentrated. The residue waspurified by reverse phase preparative HPLC using 0.05% TFA as a solventmodifier to provide the title compound (400 mg, 0.857 mmol, 82% yield)as yellow oil. LC-MS m/z 458.0 (M+H)⁺, 1.77 (ret. time)

(2S,3R)-Benzyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoateand (2R,3R)-benzyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate

(3R)-Benzyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(420 mg, 0.918 mmol) was separated with preparative HPLC under acidicconditions (with 0.1% TFA as modifier). Fractions of each peak werecombined and washed with saturated NaHCO₃ and the aqueous layer wasextracted with ethyl acetate. The combined organic layer was dried oversodium sulfate, filtered and concentrated to give the title compound(2S,3R)-benzyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(185 mg, 0.404 mmol, 44.0% yield) LC-MS m/z 458.4 (M+H)⁺, 1.06 min (ret.time) and (2R,3R)-benzyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(195 mg, 0.426 mmol, 46.4% yield) LC-MS m/z 458.5 (M+H)⁺, 1.10 min (ret.time)

(2S,3R)-Benzyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate

Thionyl chloride (46.8 mg, 0.393 mmol) was added to a solution of(2S,3R)-benzyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoate(180 mg, 0.393 mmol) in dichloromethane (0.787 mL) at ambienttemperature and the reaction stirred for 1 h. Solvent and excess thionylchloride was removed to give the title compound (184 mg, 0.386 mmol, 98%yield). LC/MS: m/z 476.0 (M+H)⁺, 1.32 min (ret. time)

(2S,3R)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methyl-3-(4-methyl-3-((2-(piperidin-1-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoicacid

[(2S,3R)-Benzyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoate(150 mg, 0.315 mmol), 1-((1H-imidazol-2-yl)methyl)piperidine (78 mg,0.473 mmol), and Hunig's base (0.165 mL, 0.945 mmol) in acetronitril(2.86 mL) were heated in a Biotage Initiator microwave reactor at 120°C. for 1 h. The solvent was removed and the crude material re-dissolvedin methanol (28.6 mL). The product was passed through an H-cube flowhydrogenation instrument at 1 mL/min through a 10% Pd/C cartridge for 2hs. The solvent was removed and the product purified by reverse phasepreparative HPLC using neutral condition to provide the title compound(30 mg, 0.058 mmol, 18.50% yield). LC/MS: m/z 515.4 (M+H)⁺, 0.84 min(ret. time)

Example 202(2R,3S)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid

(R)-4-Benzyl-3-((S)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoyl)oxazolidin-2-one

(S)-Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(2000 mg, 3.46 mmol) and Et₃N (1.446 mL, 10.38 mmol) in ethyl acetate(30 mL) was passed through a 10% Pd—C cartridge at 1 mL/minute on anH-cube flow hydrogenation instrument set on full hydrogen. After 5 h,the resulting mixture was concentrated then re-dissolved intetrahydrofuran (30.00 mL). Di(1H-Imidazol-1-yl)methanone (CDl) (841 mg,5.19 mmol) was added and the reaction stirred for 16 h. The solution wasthen diluted with ethyl acetate (20 mL) and washed with brine (4 mL) anddried (sodium sulfate). The solution was concentrated in vacuo anddissolved in acetonitrile (30.00 mL).2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepine (0.103 mL, 0.692 mmol)and (R)-4-benzyloxazolidin-2-one (919 mg, 5.19 mmol) were added and thesolution stirred at ambient temperature for 18 h. The reaction wasquenched with water and extracted with ethyl acetate (3×20 mL). Thecombined organic fractions were washed with brine and concentrated. Theproduct was purified by silica gel chromatography to give the titlecompound (1502 mg, 2.320 mmol, 67.1% yield). LC/MS: m/z 647.6 (M+H)⁺,1.61 min (ret. time)

(R)-4-Benzyl-3-((2R,3S)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one

(R)-4-benzyl-3-((S)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoyl)oxazolidin-2-one(1500 mg, 2.317 mmol) was dried under vacuum for 19 h then alternatelyevacuated and filled with nitrogen three times. Tetrahydrofuran (50 mL)was added and evacuated and filled with nitrogen twice. The solution wascooled to −78° C., sodium bis(trimethylsilyl)amide (1M in THF) (2.55 mL,2.55 mmol) was added and the reaction stirred at −78° C. for 20 minutes.Methyl iodide (1.449 mL, 23.17 mmol) was added and the reaction stirredat −78° C. for 30 min. The reaction was quenched with saturated aqueousammonium chloride and extracted with ethyl acetate (3×).

The combined organic fractions were washed (brine), dried (sodiumsulfate) and the solvent was removed. The crude material was purified bysilica gel chromatography (Combiflash) (pre-wet column with 0.1% Et₃N inhexane before loading crude material, product came out at 40% ethylacetate in hexane). The desired fractions were concentrated to give thetitle compound (1330 mg, 2.011 mmol, 87% yield). LC/MS: m/z 661.6(M+H)⁺, 1.70 min (ret. time)

(R)-4-Benzyl-3-((2R,3S)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoyl)oxazolidin-2-one

HCl in dioxane (4N) (0.603 mL, 2.413 mmol) was added to a solution of(R)-4-benzyl-3-((2R,3S)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one(1330 mg, 2.011 mmol) in methanol (20 mL). The reaction was stirred for20 minutes at which time the reaction was complete. The reaction mixturewas concentrated. The crude product was purified by silica gelchromatography (Combiflash) to give the title compound (1.07 g, 1.956mmol, 97% yield). LC/MS: m/z 547.4 (M+H)⁺, 1.18 min (ret. time)

(R)-4-Benzyl-3-((2R,3S)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoyl)oxazolidin-2-one

To a mixture of(R)-4-benzyl-3-((2R,3S)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one(120 mg, 0.186 mmol) in dichloromethane (3.00 mL) was added thionylchloride (0.027 mL, 0.372 mmol). The mixture was stirred at ambienttemperature for 1 h. The resulting mixture was concentrated to give(R)-4-benzyl-3-((2R,3S)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(chloromethyl)-4-methylphenyl)-2-methylpropanoyl)oxazolidin-2-one.This was re-dissolved in acetonitrile (3 mL),2,2-dimethyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (66.3 mg,0.372 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.098 mL, 0.558 mmol)were added. The reaction was heated via microwave reactor at 120° C. for1 h. The solvent was removed. The crude product was purified by silicagel chromatography (Combiflash) to give the title compound (81 mg, 0.115mmol, 78% yield). LC/MS: m/z 707.7 (M)⁺, 1.15 min (ret. time)

(2R,3S)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid

To a mixture of(R)-4-benzyl-3-((2R,3S)-3-(4-chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoyl)oxazolidin-2-one(81 mg, 0.115 mmol) in tetrahydrofuran (2 mL) and water (0.5 mL)THF/Water (4:1) was added hydrogen peroxide (0.094 mL, 0.916 mmol) and2M lithium hydroxide (0.172 mL, 0.344 mmol). The reaction was stirredfor 2 hs. The reaction was quenched with saturated ammonium chloride (5mL) and extracted with ethyl acetate twice. The combined organic layerwas concentrated then purified with preparative HPLC under neutralconditions to give the title compound (11 mg, 0.020 mmol, 17.52% yield)as solid. LC/MS: m/z 548.3 (M+H)+, 0.86 min (ret. time)

Example 203(2R,3S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid, 0.2 formic acid salt

A mixture of 2,2-dimethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine(43.4 mg, 0.243 mmol) and DIEA (0.142 mL, 0.812 mmol) in acetonitrile (3mL) was heated via microwave for 1 h at 120° C. The resulting mixturewas concentrated and then purified by silica gel chromatography (productcame out at 80% ethyl acetate in hexane). The desired fractions wereconcentrated under reduced pressure to give (2R,3S)-benzyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoate.This was dissolved in ethyl acetate (5 mL) and passed through an H-Cube(10% Pd/C cartridge; 1 mL/min flowrate; 25 degree) for 1 h. Theresulting mixture was concentrated and purified by reverse phasepreparative HPLC using formic acid as a solvent modifier to provide thetitle compound (13 mg, 0.025 mmol, 12.25% yield). LC/MS: m/z 514.5 (M)⁺,0.94 min (ret. time)

Example 204(R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, 0.5 Ethanol

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate(2.89 g, 5.34 mmol) in methanol at 25° C. was added 2M LiOH (16.01 ml,32.0 mmol). The reaction mixture was heated via microwave for 2 h at120° C. The reaction was acidified with 6 N HCl (pH 1). It was extractedwith ethyl acetate twice. The aqueous layer was then basified withsaturated NaHCO₃ to pH 5. It was extracted with ethyl acetate twice. Theorganic layer was washed with water twice and then brine. The resultingmixture was concentrated to give the crude product. The water layer wasextracted with 4:1 DCM and IPA to obtain another batch. Both batcheswere purified by reverse phase preparative HPLC using formic acid as asolvent modifier to give the racemic material. The crude product waspurified by chiral purification (Column: Chiralpak AD 20×250 mm, 5 u;Co-solvent: 20% EtOH; Flowrate: 50 g/min; Back pressure: 100 Bar) togive(S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, 0.3 Ethanol (783 mg, 1.446 mmol, 27.1% yield) (chiral SFC ret.time: 7.52 min) LC-MS m/z 528.3 (M+H)⁺, 0.83 min (ret. time) and(R)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid (562 mg, 1.065 mmol, 19.96% yield) (chiral SFC ret. time: 10.26min) LC-MS m/z 528.3 (M+H)⁺, 0.83 min (ret. time).

Example 205(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-N-(methylsulfonyl)propanamide,Trifluoroacetic acid salt

To a solution of(S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid (60 mg, 0.114 mmol) in dichloromethane (3 mL) at ambienttemperature was added EDC (65.4 mg, 0.341 mmol), DMAP (41.7 mg, 0.341mmol), and DIEA (0.119 mL, 0.682 mmol). The reaction mixture was stirredunder nitrogen for 15 minutes after which methanesulfonamide (54.1 mg,0.569 mmol) in DCM (0.5 mL) was added. The reaction mixture was stirredat ambient temperature for 72 h. More methanesulfonamide (54.1 mg, 0.569mmol), EDC (65.4 mg, 0.341 mmol), DMAP (41.7 mg, 0.341 mmol), and DIEA(0.119 mL, 0.682 mmol) were added and the reaction stirred at 50° C. for4 days. The reaction was quenched with saturated NH₄Cl and extractedwith DCM twice. The combined organic layer was washed with brine andconcentrated. The reaction mixture was purified with preparative HPLCunder acidic conditions (0.1% TFA as modifier) to give the titlecompound (15 mg, 0.021 mmol, 18.35% yield) as solid. LC-MS m/z 605.7(M+H)⁺, 0.67 min (ret. time)

Example 206rel-(R)-3-(3-((2,2-Dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid [enantiomer A (first to elute from SFC)]

Example 207rel-(R)-3-(3-((2,2-Dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid [enantiomer B (second to elute from SFC)]

Methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(414 mg, 1 mmol), 2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(266 mg, 1.500 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.699 ml,4.00 mmol) in acetonitrile (2 ml) were heated to 120° C. via microwavefor 1 h. The solvent was then removed under a stream of nitrogen at 50°C. The crude product was re-dissolved in water (1 mL) and methanol (2mL) and lithium hydroxide (479 mg, 20.00 mmol) was added. The solutionwas heated to 130° C. in a Biotage Initiator microwave for 3 h. DMSO (2mL) was added to the solution and the methanol and water removed with aV-10 vortex evaporator. The DMSO solution was then acidified with 1 NHCl to pH 2. The water was removed and the DMSO filtered and purified byreverse phase preparative HPLC using 0.1% TFA as a solvent modifier toprovide the racemic compound (450 mg). It was then resolved by SFC(Column: Chiralpak IF 20×250 mm, 5 u; Co-solvent: 25% MeOH; Flowrate: 50g/min; Back pressure: 100 Bar) to giverel-(R)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid (144 mg, 0.266 mmol, 26.6% yield) [enantiomer A (first to elutefrom SFC)] LC/MS: m/z 541.3 (M+H)⁺, 0.94 min (ret. time) (chiral SFCret. time: 6.02 min) andrel-(R)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid (177 mg, 0.327 mmol, 32.7% yield) [enantiomer B (second to elutefrom SFC)] LC/MS: m/z 541.3 (M+H)⁺, 0.93 min (ret. time) (chiral SFCret. time: 7.47 min).

Example 208(2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid, 2 Trifluoroacetic acid salt

(E)-Ethyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate

A mixture of tri-o-tolylphosphine (1.724 g, 5.66 mmol), ethyl acrylate(7.09 g, 70.8 mmol), 5-bromo-1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazole(8.5 g, 35.4 mmol), PdOAc₂ (0.636 g, 2.83 mmol), K₂CO₃ (9.79 g, 70.8mmol) and N,N-dimethylformamide (200 mL) was stirred at 120° C. for 12h. The mixture was poured into water and extracted with ethyl acetate(3×30 mL).

The organic layer was dried and concentrated. The isolute-adsorbed crudeproduct was purified by silica gel chromatography (hexane:ethylacetate=4:1). Desired fractions were concentrated to give the titlecompound (7.24 g, 27.9 mmol, 79% yield) as a solid. LC-MS: 262.0 (M+H)⁺,1.71 min (ret. time).

Benzyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

(3-(Hydroxymethyl)-4-methylphenyl)boronic acid (3.49 g, 21.05 mmol) wasadded to a solution of (E)-benzyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (6.15 g,19.14 mmol) and triethylamine (8.00 mL, 57.4 mmol) in dioxane (144 mL)and water (47.8 mL). The solution was degassed with Argon for 30minutes. Chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.472 g, 0.957mmol) was then added and the solution stirred at 90° C. under nitrogenfor 5 hs. The solution was then extracted with ethyl acetate (3×50 mL).The combined organic fraction was washed with brine, dried over sodiumsulfate, filtered and concentrated. The crude product was purified bysilica gel chromatography to give the title compound (6.15 g, 13.87mmol, 72.5% yield). LC/MS: m/z 444.0 (M+H)⁺, 1.12 min (ret. time) 1H NMR(400 MHz, CHLOROFORM-d) d=7.36 (s, 1H), 7.30-7.18 (m, 5H), 7.14-7.03 (m,4H), 5.01 (s, 3H), 4.68-4.59 (m, 4H), 3.27-3.06 (m, 2H), 2.82 (s, 3H),2.29 (s, 3H), 1.74 (br. s., 1H), 1.61 (t, J=7.3 Hz, 3H).

Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

1H-Imidazole (1.477 g, 21.69 mmol) and tert-butylchlorodimethylsilane(3.02 g, 20.02 mmol) were added to a solution of benzyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate(7.4 g, 16.68 mmol) in dichloromethane (33.4 mL) at ambient temperature.The solution was stirred for 2 hs and then quenched with water,extracted with DCM (3×), washed (brine) and dried (sodium sulfate). Theproduct was purified by silica gel chromatography to give the titlecompound (8.38 g, 15.02 mmol, 90% yield). LC/MS: m/z 558.2 (M+H)⁺, 1.71min (ret. time)

(S)-Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoateand (R)-benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(10 g, 17.93 mmol) was separated by Chiral SFC (Column: Chiralpak IA20×250 mm, 5 u; Co-solvent: 20% EtOH; Flowrate: 50 g/min; Back pressure:100 Bar) to give a single enantiomerically pure (S)-benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(3.7 g, 6.63 mmol, 46.3%) (chiral SFC ret. time: 3.42 min). LC/MS: m/z558.3 (M+H)⁺, 1.70 min (ret. time) and (R)-benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(3.77 g, 6.76 mmol, 47.1%) (chiral SFC ret. time: 6.18 min). LC/MS: m/z558.4 (M+H)⁺, 1.71 min (ret. time)

(S)-3-(3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

(S)-Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(3.7 g, 6.63 mmol) in methanol (221 mL) was passed through an H-cubeflow reactor with a 10% Pd—C cartridge for 7 h at 1 mL/min on full H₂mode. The methanol was removed in vacuo and the product purified bysilica gel chromatography to give the title compound (2.1 g, 4.49 mmol,67.7% yield). LC/MS: m/z 468.3 (M+H)⁺, 1.38 min (ret. time)

(R)-4-Benzyl-3-((S)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoyl)oxazolidin-2-one

Di(1H-Imidazol-1-yl)methanone (1.092 g, 6.74 mmol) was added to asolution of(S)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (2.1 g, 4.49 mmol) in tetrahydrofuran (112 mL) and the reactionstirred at ambient temperature for 16 hs. Water was added and thesolution was extracted with ethyl acetate (3×). The combined organicfractions were washed (brine), dried (sodium sulfate), filtered andconcentrated. The crude intermediate was re-dissolved in acetonitrile(112 mL), (R)-4-benzyloxazolidin-2-one (0.875 g, 4.94 mmol) and2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.135 ml, 0.898 mmol)were added and the solution stirred at ambient temperature for 16 hs.The reaction was quenched with water and extracted with ethyl acetate(3×). The combined organic fractions were washed (brine), dried (sodiumsulfate), filtered and concentrated. The product was purified by silicagel chromatography to give the title compound (1.43 g, 2.281 mmol, 50.8%yield). LC/MS: m/z 627.2 (M+H)⁺, 1.62 min (ret. time)

(R)-4-Benzyl-3-((2R,3S)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one

Sodium bis(trimethylsilyl)amide (2.457 ml, 2.457 mmol) was addeddropwise to a solution of(R)-4-benzyl-3-((S)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoyl)oxazolidin-2-one(1.4 g, 2.233 mmol) in tetrahydrofuran (22.33 mL) at −78° C. and thereaction stirred for 30 minutes. Methyl iodide (5.58 mL, 11.17 mmol) wasthen added and the solution stirred for 3 h at −78° C. and then warmedto ambient temperature. The reaction was quenched with saturated aqueousammonium chloride and extracted with ethyl acetate (3×). The combinedorganic fractions were washed (brine), dried (sodium sulfate), filteredand concentrated. The crude product was purified by silica gelchromatography to give the title compound (1.22 g, 1.904 mmol, 85%yield). LC/MS: m/z 641.1(M+H)⁺, 1.70 min (ret. time)

(R)-4-Benzyl-3-((2R,3S)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoyl)oxazolidin-2-one

HCl (234 μL, 1.404 mmol) was added to a solution of(R)-4-benzyl-3-((2R,3S)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one(300 mg, 0.468 mmol) in methanol (4.68 mL) and the reaction stirred for5 minutes at which time the reaction was complete. The solution wasfiltered over sodium sulfate, filtered and concentrated to give thetitle compound (247 mg, 0.468 mmol, 100% yield). LC/MS: m/z 527.4(M+H)⁺, 1.19 min (ret. time)

(R)-4-Benzyl-3-((2R,3S)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one

Thionyl chloride (41.6 μL, 0.570 mmol) was added to a solution of(R)-4-benzyl-3-((2R,3S)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpropanoyl)oxazolidin-2-one(100 mg, 0.190 mmol) in dichloromethane (1.9 mL) and the reactionstirred for 30 minutes. Solvent and excess thionyl chloride was removed.The crude chloride intermediate was then added to a solution of2,2-dimethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine hydrochloride(82 mg, 0.380 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.570mmol) in acetonitrile (1.9 mL) and heated in a Biotage Initiatormicrowave reactor at 120° C. for 1 h. The solvent was removed andpurified by silica gel chromatography to give the title compound (66 mg,0.096 mmol, 50.6% yield). LC/MS: m/z 687.6 (M+H), 1.19 min (ret. time)

(2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid, 2 Trifluoroacetic acid salt

To a solution of(S)-4-benzyl-3-((2R,3R)-3-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one(100 mg, 0.146 mmol) in tetrahydrofuran (1.67 mL) and water (417 μl) atambient temperature were added hydrogen peroxide (119 μL, 1.166 mmol)followed by lithium hydroxide (0.437 mL, 0.437 mmol). The reaction wasstirred for 2 h. The reaction was quenched with saturated aqueousammonium chloride (2 mL) and extracted with ethyl acetate (3×5 mL). Thecombined organic layer was dried over sodium sulfate, filtered andconcentrated. The crude product was purified by reverse phasepreparative HPLC using 0.1% TFA as a solvent modifier to provide thetitle compound (35 mg, 0.046 mmol, 31.8% yield). LC/MS: m/z 527.4(M+H)⁺, 0.89 min (ret. time)

Example 209(2R,3S)-3-(7-Chloro-1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid

To a solution of(S)-4-benzyl-3-((2R,3S)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one(80 mg, 0.116 mmol) in tetrahydrofuran (1.86 mL) and water (466 μL) atambient temperature were added hydrogen peroxide (47.6 μL, 0.466 mmol)followed by lithium hydroxide (0.175 mL, 0.175 mmol). The reaction wasstirred for 2 h. The reaction was quenched with 4 N HCl in diethylether. The compound was purified by reverse phase preparative HPLC using0.1% TFA as a solvent modifier. The title compound (13 mg, 0.023 mmol,19.86% yield) was obtained. LC/MS: m/z 562.2 (M+H)⁺, 0.99 min (ret.time)

Example 210(2R,3S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methyl-3-(4-methyl-3-((2-(piperidin-1-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoicacid

[(R)-4-Benzyl-3-((2R,3S)-3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoyl)oxazolidin-2-one(200 mg, 0.367 mmol), 1-((1H-imidazol-2-yl)methyl)piperidine (91 mg,0.550 mmol), and Hunig's base (96 μL, 0.550 mmol) in acetonitrile (4 mL)were heated in a Biotage Initiator microwave reactor at 120° C. for 1 h.The solvent was removed and the crude material re-dissolved intetrahydrofuran (4.1 mL) and water (1 mL). The solution was cooled to 0°C. and hydrogen peroxide (0.150 mL, 1.468 mmol) followed by lithiumhydroxide (0.55 mL, 0.550 mmol) were added and the solution stirred at0° C. for 2 hs. The reaction was quenched with saturated aqueousammonium chloride (5 mL) and extracted with ethyl acetate (3×15 mL). Thecombined organic fractions were dried over sodium sulfate, filtered andconcentrated. The product was purified by reverse-phase HPLC and silicagel chromatography to give the title compound (7 mg, 0.014 mmol, 3.71%yield). LC/MS: m/z 515.5 (M+H)⁺, 0.79 min (ret. time)

Example 2111-((1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)methyl)cyclopropanecarboxylicacid, Trifluoroacetic acid salt

5-(Chloro(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methyl)-1,4-dimethyl-1H-benzo[d][1,2,3]triazole

Thionyl chloride (114 μl, 1.557 mmol) was added to a solution of(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methanol(500 mg, 1.198 mmol) in dichloromethane (12 mL) at ambient temperatureand the reaction stirred for 30 minutes. Thionyl chloride was removedunder reduced pressure with to give the title compound (522 mg, 1.198mmol, 100% yield). LC/MS: m/z 418.0(M+H)⁺, 1.12 min (ret. time)

Methyl1-((1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methyl)cyclopropanecarboxylate

Chlorotrimethylsilane (34.4 μL, 0.034 mmol) was added to a suspension ofzinc (67.5 mg, 1.032 mmol) in tetrahydrofuran (1.75 μL) under a nitrogenatmosphere and the reaction stirred for 15 minutes at ambienttemperature. Methyl 1-bromocyclopropanecarboxylate (110 μL, 0.860 mmol)was added and the reaction stirred at ambient temperature for 2 hs. Thissolution was then added by syringe to a solution of5-(chloro(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methyl)-1,4-dimethyl-1H-benzo[d][1,2,3]triazole(150 mg, 0.344 mmol) in tetrahydrofuran (1.75 μL) and the reactionstirred for 45 minutes. The reaction was quenched with saturated aqueousammoium chloride (2 mL) and the mixture extracted with ethyl acetate(3×5 mL). The combined organic fractions were washed with brine anddried over sodium sulfate, filtered and concentrated. The crude productwas purified by silica gel chromatography to give the title compound(100 mg, 0.200 mmol, 58.2% yield). LC/MS: m/z 500.4 (M+H)+, 1.31 min(ret. time)

Methyl1-((3-(chloromethyl)-4-methylphenyl)(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)cyclopropanecarboxylate

DDQ (91 mg, 0.400 mmol) was added to a solution of methyl1-((1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methyl)cyclopropanecarboxylate(100 mg, 0.200 mmol) in dichloromethane (2 mL) at 0° C. and the reactionstirred for 2 hs. The reaction was quenched with saturated sodiumbicarbonate (5 mL) and extracted with ethyl acetate (4×15 mL). Thecombined organic fractions were washed (brine), dried (sodium sulfate),filtered and concentrated. The crude product was purified by silica gelchromatography to give the intermediate. This intermediate was dissolvedin dichloromethane (2 mL) and thionyl chloride (29.2 μL, 0.400 mmol) wasadded and the reaction stirred for 30 minutes. Solvent and excessthionyl chloride was removed to give the title compound (35 mg, 0.088mmol, 43.9% yield). LC/MS: m/z 398.2 (M+H)⁺, 1.19 min (ret. time)

1-((1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)methyl)cyclopropanecarboxylicacid, Trifluoroacetic acid salt

Methyl1-((3-(chloromethyl)-4-methylphenyl)(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)cyclopropanecarboxylate(35 mg, 0.088 mmol),2,2-dimethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine hydrochloride(37.8 mg, 0.176 mmol) and N-ethyl-N-isopropylpropan-2-amine (46.0 μL,0.264 mmol) in acetonitrile (1.2 mL) were heated in a Biotage Initiatormicrowave reactor at 120° C. for 1 h. The solvent was evaporated and thecrude product was re-dissolved in methanol (1.17 mL) and water (0.6 mL).The solution was heated in a Biotage Initiator microwave reactor at 130°C. for 1.5 hs. The solution was then acidified with 6 N HCl and thesolvent was removed. The crude material was dissolved in DMSO andpurified by reverse phase preparative HPLC using 0.1% TFA as a solventmodifier to provide the title compound (11.4 mg, 0.018 mmol, 20.26%yield). LC/MS: m/z 526.3 (M+H)⁺, 1.01 min (ret. time)

Example 2123-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoicacid, formic acid salt

2-(Methoxycarbonyl)-3-methylpyridine 1-oxide

3-Chlorobenzoperoxoic acid (685 mg, 3.97 mmol) was added to a solutionof methyl 3-methylpicolinate (500 mg, 3.31 mmol) in dichloromethane(8.269 mL) at 0° C. The solution was allowed to warm to ambienttemperature stirring for a total of 12 hs. The product was purified bysilica gel chromatography to give the title compound (538 mg, 3.22 mmol,97% yield). LC/MS: m/z 167.8 (M+H)⁺, 0.43 min (ret. time). ¹H NMR (400MHz, CHLOROFORM-d) b 8.14-8.10 (m, 1H), 7.26-7.19 (m, 1H), 7.17-7.12 (m,1H), 4.05 (s, 3H), 2.32 (s, 3H)

Methyl 6-bromo-3-methylpicolinate

Phosphoryl tribromide (17.15 g, 59.8 mmol) was added to a solution of2-(methoxycarbonyl)-3-methylpyridine 1-oxide (5 g, 29.9 mmol) in1,2-dichloroethane (100 mL) and heated to 84° C. for 4 hs. The solutionwas cooled to 0° C. and quenched slowly with water (50 mL) and extractedwith DCM (3×100 mL). The combined organic fractions were washed withwater (50 mL), saturated aqueous sodium bicarbonate (50 mL), dried oversodium sulfate, filtered and concentrated. The crude product waspurified by silica gel chromatography to give the title compound (600mg, 2.61 mmol, 8.72% yield). LC/MS: m/z 229.8, 231.8 (M+H)+, 0.82 min(ret. time). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.58-7.44 (m, 2H), 3.98(s, 3H), 2.55 (s, 3H)

6-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methylpyridine

Diisobutylaluminum hydride (6.520 mL, 6.52 mmol) was added dropwise to asolution of methyl 6-bromo-3-methylpicolinate (600 mg, 2.61 mmol) intetrahydrofuran (13.04 mL) at −45° C. After 1 h, the reaction wasquenched with methanol (5 mL) and the solvent removed in vacuo. Thecrude product was dissolved in dichloromethane (13.04 mL),tert-butyldimethyl chlorosilane (786 mg, 5.22 mmol) and imidazole (391mg, 5.74 mmol) were added at ambient temperature. The reaction wascomplete in 1 h and was quenched with water (5 mL) and extracted withDCM (3×10 mL). The combined organic fractions were washed (brine) anddried over sodium sulfate. The crude residue was purified by silica gelchromatography to give the title compound (200 mg, 0.632 mmol, 24.24%yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.33 (s, 1H), 7.29 (s, 1H),4.80 (s, 2H), 2.38 (s, 3H), 0.92 (s, 9H), 0.11 (s, 6H)

(6-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol

n-Butyllithium (543 μL, 0.869 mmol) was added to a solution of6-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methylpyridine (250mg, 0.790 mmol) in diethyl ether (7.9 mL) at −78° C. and the reactionstirred for 20 minutes.1,4-Dimethyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde (152 mg, 0.869mmol) in diethyl ether (8 mL) was then added by syringe and the solutionstirred at −78° C. for 30 minutes before allowing to warm to ambienttemperature. The reaction was quenched with saturated aqueous ammoniumchloride and the solution was extracted with dichloromethane (3×25 mL).The combined organic layer was washed with brine (10 mL), dried (sodiumsulfate), filtered and concentrated. The crude residue was purified bysilica gel chromatography to give the title compound (163 mg, 0.395mmol, 50% yield). LC/MS: m/z 413.1 (M+H)⁺, 0.99 min (ret. time)

Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate

2,2,2-Trichloroacetonitrile (77 μL, 0.771 mmol) and2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (2.66 μL, 0.019 mmol)were added sequentially to a solution of(6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol(159 mg, 0.385 mmol) in acetonitrile (0.3 mL) at ambient temperature andthe reaction stirred for 45 minutes.((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (0.157 mL, 0.771mmol) followed by1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (10.83mg, 0.039 mmol) were added and the solution stirred at ambienttemperature for 2 h. The reaction was quenched with saturated sodiumbicarbonate (10 mL) and extracted with DCM (3×15 mL), dried over sodiumsulfate, filtered and concentrated. The residue was re-dissolved intetrahydrofuran (0.3 mL). The solution was cooled to 0° C. and TBAF (771μL, 0.771 mmol) was added. The solution was stirred at 0° C. for 1 h atwhich time LC-MS showed the reaction was complete. The reaction wasquenched with saturated sodium bicarbonate (10 mL) and extracted withDCM (3×15 mL) and dried over sodium sulfate. The crude product waspurified by silica gel chromatography to give the title compound (103mg, 0.270 mmol, 70% yield). LC/MS: m/z 383.0 (M+H)⁺, 0.83 min (ret.time)

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoicacid, formic acid salt

Thionyl chloride (8.02 μL, 0.110 mmol) was added to a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate(21 mg, 0.055 mmol) in dichloromethane (0.39 mL) at ambient temperatureand the reaction stirred for 30 minutes. The solvent and excess thionylchloride was removed to give the benzyl chloride intermediate. This wasdissolved in acetonitrile (0.392 mL),(R)-2-ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine hydrochloride(17.68 mg, 0.082 mmol) and Hunig'sbase (29 μL, 0.165 mmol) were addedand the mixture heated via microwave reactor at 120° C. for 2 hs. Theresulting mixture was concentrated. The crude product was re-dissolvedin methanol (0.392 mL) and water (0.196 mL). Lithium hydroxide (26.3 mg,1.098 mmol) was added and the solution heated via microwave reactor at130° C. for 1.5 hs. The reaction was acidified with 6N HCl and thesolvent removed. The crude product was dissolved in DMSO (1 mL),filtered and purified by reverse phase preparative HPLC using formicacid as a solvent modifier to provide the title compound (16 mg, 0.028mmol, 50.7% yield). LC/MS: m/z 529.3 (M+H)⁺, 0.72 min (ret. time)

Example 2133-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoicacid, Trifluoroacetic acid salt

(5-Bromo-2-methylpyridin-3-yl)methanol

To a solution of ethyl 5-bromo-2-methylnicotinate (5 g, 20.48 mmol) intetrahydrofuran (50 mL) was added LAH (0.855 g, 22.53 mmol) at 0° C. Themixture was stirred at 0° C. for 1 h, and then 0.63 mL water was added.Then 0.63 ml 10% NaOH and 1.89 mL water were added. The mixture wasfiltered and the filtrate was concentrated. The residue was purified bysilica gel chromatography (PE:EA=1:1) to give the title compound (3 g,14.85 mmol, 72.5% yield) as a yellow solid. LCMS: m/z 203.9 (M+H)⁺, 1.17min (ret.)

5-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylpyridine

Tert-butyldimethylchlorosilane (746 mg, 4.95 mmol) and imidazole (371mg, 5.44 mmol) were added to a solution of(5-bromo-2-methylpyridin-3-yl)methanol (500 mg, 2.475 mmol) indichloromethane (4.949 mL) at ambient temperature and the reactionstirred for 1 h. The reaction was quenched with water (5 mL) andextracted with DCM (3×10 mL). The combined organic fraction was washed(brine), dried (sodium sulfate), filtered and concentrated. The cruderesidue was purified by silica gel chromatography to give the titlecompound (758 mg, 2.396 mmol, 97% yield). LC/MS: m/z 315.9, 317.9(M+H)⁺, 1.39 min (ret. time)

(5-(((tert-Butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol

n-Butyllithium (1.498 mL, 2.397 mmol) was added to a solution of5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylpyridine (758mg, 2.397 mmol) in tetrahydrofuran (11.416 mL) at −78° C. and thereaction stirred for 30 minutes.1,4-Dimethyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde (280 mg, 1.598mmol) in tetrahydrofuran (2.0 mL) was added dropwise and the reactionstirred for 30 minutes before allowing to warm to ambient temperature.The reaction was quenched with saturated ammonium chloride (5 mL) andextracted with ethyl acetate (3×10 mL). The combined organic fractionwas washed (brine), dried (sodium sulfate), filtered and concentrated.The crude residue was purified by silica gel chromatography to give thetitle compound (519 mg, 1.258 mmol, 79% yield). LC/MS: m/z 413.1 (M+H)+,0.94 min (ret. time)

Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate

2,2,2-Trichloroacetonitrile (252 μl, 2.52 mmol) and2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (8.70 μL, 0.063 mmol)were added sequentially to a solution of(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol(519 mg, 1.258 mmol) in acetonitrile (1.3 mL) at ambient temperature andthe reaction stirred for 45 minutes.((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (511 μL, 2.52mmol) followed by1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (35.4mg, 0.126 mmol) were then added and the solution stirred at ambienttemperature for 2 hs. LC-MS showed the starting material was consumedwith the major product being TBS protected intermediate (LC-MS: m/z497.2 (M+H)+, 1.08 min (ret. time)). The reaction was quenched withsaturated sodium bicarbonate (10 mL) and extracted with DCM (3×15 mL),dried over sodium sulfate, filtered and concentrated then re-dissolvedin tetrahydrofuran (1.3 mL). The solution was cooled to 0° C. and TBAF(2.5 mL, 2.52 mmol) was added. The solution was stirred at 0° C. for 2h. The reaction was quenched with saturated sodium bicarbonate (10 mL)and extracted with DCM (3×15 mL), dried over sodium sulfate, filteredand concentrated. The crude product was purified by silica gelchromatography to give the title compound (182 mg, 0.476 mmol, 37.8%yield). LC/MS: m/z 383.1 (M+H)⁺, 0.63 min (ret. time)

Methyl3-(5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

Thionyl chloride (0.069 mL, 0.952 mmol) was added to a solution ofmethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate(182 mg, 0.476 mmol) in dichloromethane (2.379 mL) at ambienttemperature. The solution was stirred for 30 minutes and the DCM wasconcentrated. The excess thionyl chloride was removed under reducedpressure to give the title compound (191 mg, 0.476 mmol, 100% yield).LC/MS: m/z 401.0 (M+H)+, 0.77 min (ret. time)

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoicacid, trifluoroacetic acid salt

A mixture of methyl3-(5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(60 mg, 0.150 mmol),(R)-2-ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine hydrochloride(48.2 mg, 0.224 mmol), and Hunig'sbase (105 μl, 0.599 mmol) inacetonitrile (1497 μL) was heated via microwave reactor at 120° C. for 2hs. The solvent was removed and the residue re-dissolved in methanol(1497 μL) and water (748 μL). Lithium hydroxide (71.7 mg, 2.99 mmol) wasadded and the reaction heated via microwave reactor at 120° C. for 1 h.The solution was acidified with 6N HCl and the solvent was removed. Thecrude product was purified by reverse phase preparative HPLC using 0.1%TFA as a solvent modifier to provide the title compound (26 mg, 0.040mmol, 27.0% yield). LC/MS: m/z 529.2 (M+H)⁺, 0.60 min (ret. time)

Example 2143-(5-((2-(Cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-6-methylpyridin-3-yl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid, Trifluoroacetic acid salt

A solution of sodium hydride (14.37 mg, 0.599 mmol), methyl3-(5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(60 mg, 0.150 mmol), and 2-(cycloheptylmethyl)-1H-imidazole (40.0 mg,0.224 mmol) in N,N-dimethylformamide (1497 μL) was kept at ambienttemperature for 2 hs. The reaction was quenched with methanol and thenthe solvent was removed. The crude material was re-dissolved in methanol(1497 μL) and water (748 μL). Lithium hydroxide (143 mg, 5.99 mmol) wasadded and the solution heated via microwave reactor at 120° C. for 1 h.The solution was acidified with 6N HCl and the solvent concentrated. Thecrude product was purified by reverse phase preparative HPLC using 0.1%TFA as a solvent modifier to provide the title compound (17.5 mg, 0.027mmol, 18.19% yield). LC/MS: m/z 529.1 (M+H)⁺, 0.73 min (ret. time).

Example 215(3S)-3-(3-((3-((1H-Pyrazol-1-yl)methyl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

tert-Butyl 3-((1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

To a solution of tert-butyl 3-(bromomethyl)piperidine-1-carboxylate (680mg, 2.444 mmol) and 1H-pyrazole (183 mg, 2.69 mmol) inN,N-dimethylformamide (5 mL) was added NaH (196 mg, 4.89 mmol)portionwise with vigorous stirring. The reaction mixture was heated in aBiotage microwave at high absorption for 5 h at 100° C. The reactionmixture was quenched with water and extracted with EtOAc, washed withbrine. The organic layer was dried over MgSO₄ and concentrated to givethe title compound (600 mg, 2.261 mmol, 93% yield). LC/MS: m/z 266.1(M+H)+, 0.94 min (ret. time).

3-((1H-Pyrazol-1-yl)methyl)piperidine, 2Hydrochloride

Dissolve tert-butyl 3-((1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate(600 mg, 2.261 mmol) in HCl in dioxane (4 M) (5 mL, 165 mmol). Thesolution was stirred in room temperature for 1 h. The solvent wasremoved and the residue was washed by EtOAc to give the title compound(539 mg, 2.261 mmol, 100% yield). LC/MS: m/z 166.0 (M+H)⁺, 0.41 min(ret. time).

(3S)-3-(3-((3-((1H-Pyrazol-1-yl)methyl)piperidin-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

To a solution of (S)-ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(100 mg, 0.259 mmol) and 3-((1H-pyrazol-1-yl)methyl)piperidine,2Hydrochloride (185 mg, 0.777 mmol) in Acetonitrile (3 mL) was addedDIEA (0.362 mL, 2.073 mmol). The reaction mixture was heated in aBiotage microwave at high absorption for 1 h at 120° C. The solvent wasremoved under vacum and residue was dissolved in ethanol (3.00 mL). NaOH(6M) (0.432 mL, 2.59 mmol) was added. The mixture was heated in aBiotage microwave at high absorption for 20 min at 120° C. The crudeproduct was purified by reverse phase preparative HPLC using 0.1% formicacid as a solvent modifier to provide the title compound (90 mg, 0.176mmol, 67.8% yield). LC/MS: m/z 487.4 (M+H)⁺, 0.68 min (ret. time).

Example 2165-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate

To a solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpentanoate(0.050 g, 0.115 mmol) in dichloromethane (DCM) (2.00 mL) was addedthionyl chloride (0.017 mL, 0.230 mmol) and the reaction stirred atambient temperature for 30 min. The solvent was removed and the residue,in acetonitrile (1.00 mL), was added to a solution of(R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine (0.023 g,0.115 mmol) and DIEA (0.080 mL, 0.459 mmol) in acetonitrile (2.00 mL) ina 10 mL microwave reaction vessel. The reaction was heated in amicrowave to 120^(□)C for 1 h afterwhich, additional(R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine (0.005 g,0.028 mmol) was added and the solution heated via microwave at 120^(□□)Cfor 20 min. Isolute was added to the reaction and the solvent wasremoved. The residue was purified by flash chromatography eluting with0-40-50% (3:1 EtOAc:EtOH)/hexane to provide the title compound. (0.035g, 44% yield) LC/MS m/z=596 (M+H)⁺, 1.07 min (ret.time).

5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid

A solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(0.035 g, 0.051 mmol) in methanol (10 mL) was hydrogenated on H-Cubeusing 10% Pd/C cartridge and full H₂ pressure for 1 h. The solvent wasremoved and the residue was purified by reverse phase preparative HPLCunder neutral conditions to provide the title compound. (0.009 g, 35%yield) LC/MS m/z=506 (M+H)⁺, 0.84 min (ret. time).

Example 2175-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid

(2-Bromopyridin-3-yl)methanamine

To a solution of 2-bromo-3-(bromomethyl)pyridine, hydrochloride inethanol (20 mL) heated at 50° C., was added ammonium hydroxide dropwiseand stirred at 50° C. for 2 h The solvent was removed and the residuewas pumped on high vacuum. The residue was then triturated withdichloromethane and the solid was filtered. The filtered solid waspurified by flash chromatography eluting with 0-50% (10%NH₄OH-MeOH/DCM)/DCM to provide the title compound. (1.32 g, 59% yield)LC/MS m/z=187 (M+H)⁺, 0.16 min (ret.time).

(R)-1-(((2-Bromopyridin-3-yl)methyl)amino)butan-2-ol

A solution of (2-bromopyridin-3-yl)methanamine (1.27 g, 6.79 mmol) and(R)-2-ethyloxirane (0.490 g, 6.79 mmol) in ethanol (10 mL) in a 20 mLmicrowave reaction vessel was heated via microwave at 150° C. for 2hours. The solvent was removed and the residue was purified by flashchromatography eluting with 0-50-90% of (3:1 EtOAc:EtOH)/hexane toprovide the title compound. (0.934 g, 53% yield) LC/MS m/z=259 (M+H)⁺,0.42 min (ret.time).

(R)-2-Ethyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine

To a solution of (R)-1-(((2-bromopyridin-3-yl)methyl)amino)butan-2-ol(1.365 g, 5.27 mmol) in N,N-dimethylformamide (DMF) (20 mL) was addedpotassium tert-butoxide (1.773 g, 15.80 mmol) and the reaction heated to80° C. for 1.5 h. The reaction was cooled, the solids were filtered andwashed with DMF and then the solvent was removed. The residue waspurified by flash chromatography eluting with 0-5% MeOH/DCM to providethe title compound. (0.89 g, 95% yield) LC/MS m/z=179 (M+H)⁺, 0.23 min(ret.time).

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate

To a solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpentanoate(0.041 g, 0.094 mmol) in dichloromethane (DCM) (2.00 mL) was addedthionyl chloride (0.014 mL, 0.188 mmol) and the reaction stirred atambient temperature for 30 min. The solvent was removed and the residue,in acetonitrile (1.00 mL), was added to a solution of(R)-2-ethyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.019 g,0.094 mmol) and DIEA (0.066 mL, 0.377 mmol) in acetonitrile (2.000 mL)in a 10 mL microwave reaction vessel. The reaction was heated in amicrowave to 120° C. for 1 h. The solvent was removed and the residuewas purified by flash chromatography eluting with 0-40-50% (3:1EtOAc:EtOH)/hexane to provide the title compound. (0.038 g, 67% yield)LC/MS m/z=596 (M+H)⁺, 1.03 min (ret.time).

5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid

A solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(0.038 g, 0.064 mmol) in methanol (10 mL) was hydrogenated on H-Cubeusing 10% Pd/C cartridge and full H₂ pressure, for 1.5 h. The solventwas removed and the residue was purified by reverse phase preparativeHPLC under neutral conditions to provide the title compound. (0.008 g,24% yield) LC/MS m/z=506 (M+H)⁺, 0.77 min (ret. time).

Example 218(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, Trifluoroacetate

(S)-Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

To a solution of (S)-methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(0.100 g, 0.262 mmol) in dichloromethane (DCM) (3.00 mL) was addedthionyl chloride (0.040 mL, 0.546 mmol) and the reaction stirred atambient temperature for 30 min. The solvent was removed and the residue,in acetonitrile (2.00 mL), was added to a solution of(R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine (0.054 g,0.273 mmol) and DIEA (0.183 mL, 1.049 mmol) in acetonitrile (3.00 mL) ina 10 mL microwave reaction vessel. The reaction was heated in microwaveto 120° C. for 1 h. Isolute was added to the reaction and the solventwas removed. The residue was purified by flash chromatography elutingwith 0-30% (3:1 EtOAc:EtOH)/hexane to provide the title compound. (0.087g, 61% yield) LC/MS m/z=542 (M+H)⁺, 1.02 min (ret.time).

(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, Trifluoroacetate

To a solution of (S)-methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate(0.087 g, 0.161 mmol) in tetrahydrofuran (THF) (2 mL), methanol (2.000mL) and water (2.000 mL) in a 10 mL microwave reaction vessel was addedlithium hydroxide (0.038 g, 1.606 mmol) and the solution heated viamicrowave at 150° C. for 1 h. The reaction was acidified withtrifluoroacetic acid and, the solvent was removed and the residue waspurified by reverse phase preparative HPLC using TFA as a solventmodifier to provide the title compound. (0.097 g, 94% yield) LC/MSm/z=528 (M+H)⁺, 0.88 min (ret. time).

Example 219(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, Trifluoroacetate

(S)-Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

To a solution of (S)-methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(0.100 g, 0.262 mmol) in dichloromethane (DCM) (3.00 mL) was addedthionyl chloride (0.038 mL, 0.524 mmol) and the reaction stirred atambient temperature for 30 min. The solvent was removed and the residue,in acetonitrile (2.00 mL), was added to a solution of(R)-2-ethyl-2,3,4,5-tetrahydropyrido[4,3-f][1,4]oxazepine (0.052 g,0.262 mmol) and DIEA (0.183 mL, 1.049 mmol) in acetonitrile (3.00 mL) ina 10 mL microwave reaction vessel. The reaction was heated in amicrowave to 120 C for 1 h. Isolute was added to the reaction and thesolvent was removed. The residue was purified by flash chromatographyeluting with 0-30% (3:1 EtOAc:EtOH)/hexane to provide the titlecompound. (0.057 g, 39% yield) LC/MS m/z=542 (M+H)⁺, 0.98 min(ret.time).

(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid, Trifluoroacetate

To a solution of (S)-methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate(0.057 g, 0.105 mmol) in tetrahydrofuran (THF) (2 mL), methanol (2.000mL) and water (2.000 mL) in a 10 mL microwave reaction vessel was addedlithium hydroxide (0.025 g, 1.052 mmol) and the solution heated viamicrowave at 150° C. for 1 h. The reaction was acidified withtrifluoroacetic acid and, the solvent was removed and the residue waspurified by reverse phase preparative HPLC using TFA as a solventmodifier to provide the title compound. (0.054 g, 80% yield) LC/MSm/z=528 (M+H)⁺, 0.85 min (ret. time).

Example 2205-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid, 3.2 Trifluoroacetic acid salt

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate

To a solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpentanoate(0.100 g, 0.230 mmol) in dichloromethane (DCM) (3 mL) was added thionylchloride (0.034 mL, 0.459 mmol) and the reaction stirred at ambienttemperature for 30 min. The solvent was removed and the residue, inacetonitrile (2 mL), was added to a solution of(R)-2-ethyl-2,3,4,5-tetrahydropyrido[4,3-f][1,4]oxazepine (0.045 g,0.230 mmol) and DIEA (0.160 mL, 0.918 mmol) in acetonitrile (3 mL) in a10 mL microwave reaction vessel. The reaction was heated in a microwaveto 120° C. for 1 h. Isolute was added to the reaction and the solventwas removed. The residue was purified by flash chromatography elutingwith 0-40-50% (3:1 EtOAc:EtOH)/hexane to provide the title compound.(0.058 g, 41% yield) LC/MS m/z=596 (M+H)⁺, 1.07 min (ret.time).

5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid, 3.2 Trifluoroacetic acid salt

A solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(0.054 g, 0.091 mmol) in methanol (10 mL) was hydrogenated on H-Cubeusing 10% Pd/C cartridge and 50 bar H₂ pressure, for 5.5 h. The solventwas removed and the residue was purified by reverse phase preparativeHPLC using TFA as a solvent modifier to provide the title compound.(0.038 g, 48% yield) LC/MS m/z=506 (M+H)⁺, 0.82 min (ret. time).

Example 2213-(3-((2,2-Dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoicacid

Benzyl3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoate

To a solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpentanoate(0.050 g, 0.115 mmol) in dichloromethane (DCM) (3 mL) was added thionylchloride (0.017 mL, 0.230 mmol) and the reaction stirred at ambienttemperature for 30 min. The solvent was removed and the residue wasdissolved in acetonitrile (5 mL) in a 10 mL microwave reaction vessel.To this solution was added2,2-dimethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine,hydrochloride (0.027 g, 0.126 mmol) and DIEA (0.080 mL, 0.459 mmol). Thereactions were heated via microwave to 120° C. for 1 h. The solvent wasremoved and the residue was purified by flash chromatography elutingwith 0-40% (3:1 EtOAc:EtOH)/hexane to provide the title compound. (0.051g, 60% yield) LC/MS m/z=596 (M+H)⁺, 1.12 min (ret.time).

3-(3-((2,2-Dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoicacid

A solution of benzyl3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoate(0.051 g, 0.069 mmol) in methanol (10 mL) was hydrogenated on H-Cubeusing 10% Pd/C cartridge and full H₂ pressure, for 30 min. The solventwas removed and the residue was purified by reverse phase preparativeHPLC under neutral conditions to provide the title compound. (0.011 g,31% yield) LC/MS m/z=506 (M+H)⁺, 0.89 min (ret. time).

Example 222(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-6-fluoro-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid

(S)-Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-6-fluoro-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

To a solution of(R)-2-ethyl-6-fluoro-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine(0.030 g, 0.153 mmol) in acetonitrile (10.00 mL) in a 5 mL microwavereaction vessel was added (S)-methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(0.061 g, 0.153 mmol) and DIEA (0.080 mL, 0.459 mmol) and heated at 120°C. for 1 h. The solvent was removed and the residue was purified byflash chromatography eluting with 0-25-40% (3:1 EtOAc:EtOH)/hexane. toprovide the title compound. (0.056 g, 65% yield) LC/MS m/z=560 (M+H)⁺,1.01 min (ret.time).

(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-6-fluoro-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid

To a solution of (S)-methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-6-fluoro-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate(56 mg, 0.100 mmol) in, methanol (4 mL) and water (2 mL) in a 10 mLmicrowave reaction vessel, was added LiOH (11.98 mg, 0.500 mmol) and thesolution heated via microwave at 120° C. for 7 h. The reaction wasacidified with formic acid and the solvent was removed. The residue waspurified by reverse phase preparative HPLC using formic acid as asolvent modifier to provide the title compound. (0.004 g, 6.6% yield)LC/MS m/z=546 (M+H)⁺, 0.92 min (ret. time).

Example 2233-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoicacid

Benzyl3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoate

To a solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpentanoate(0.050 g, 0.115 mmol) in dichloromethane (DCM) (3 mL) was added thionylchloride (0.017 mL, 0.230 mmol) and the reaction stirred at ambienttemperature for 30 min. The solvent was removed and the residue wasdissolved in acetonitrile (5 mL) in a 10 mL microwave reaction vessel.To this solution was added2,2-dimethyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.045 g,0.126 mmol) and DIEA (0.080 mL, 0.459 mmol). The reactions were heatedvia microwave to 120° C. for 1.5 h. The solvent was removed and theresidue was purified by flash chromatography eluting with 0-40% (3:1EtOAc:EtOH)/hexane to provide the title compound. (0.055 g, 80% yield)LC/MS m/z=596 (M+H)⁺, 1.06 min (ret.time).

3-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoicacid

A solution of benzyl3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoate(0.047 g, 0.079 mmol) in methanol (10 mL) was hydrogenated on H-Cubeusing 10% Pd/C cartridge and full H₂ pressure, for 20 min. The solventwas removed and the residue was purified by reverse phase preparativeHPLC using formic acid as a solvent modifier to provide the titlecompound. (0.014 g, 35% yield) LC/MS m/z=506 (M+H)⁺, 0.81 min (ret.time).

Example 2245-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoicacid, 0.20 formic acid salt

tert-Butyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2-methyl-7-(trimethylsilyl)hept-6-ynoate

A −70^(□)C. solution of diisopropylamine (0.643 mL, 4.52 mmol) intetrahydrofuran (THF) (4.5 mL) was treated with 1.6 M n-butyllithium(1.693 mL, 2.71 mmol) and stirred at −70^(□)C. for 1 h. The reaction waswarmed to −40^(□)C. (dry-ice acetonitrile) for 10 min, and then recooledto −70^(□)C. Tert-butyl propionate (0.544 mL, 3.61 mmol) intetrahydrofuran (THF) (4.50 mL) was added to the −70^(□)C. solutiondropwise. The reaction was stirred at −70^(□)C. for 45 min, warmed to−50^(□)C. briefly, and then recooled to −70^(□)C. Afterwards,(5-bromo-5-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)pent-1-yn-1-yl)trimethylsilane(0.415 g, 0.903 mmol) in tetrahydrofuran (THF) (0.5 mL) was addeddropwise to the enolate followed by dry DMPU (2.178 mL, 18.06 mmol) andstirred at −70^(□)C. for 2 h. The reaction was then warmed to −40^(□)Cand stirred for 2 h (dry-ice acetonitrile). The reaction was quenchedwith 5 mL sat aqueous NH₄Cl, diluted with water (20 mL) and EtOAc (75mL). The phases were separated and the aqueous layer was extracted withEtOAc (50 mL). The combined organic layers were washed with water (3×25mL), saturated NaCl (25 mL) and then dried with Na₂SO₄. The solvent wasremoved and the residue was purified by flash chromatography elutingwith 0-10% EtOAc/hexane to provide the title compound. (0.189 g, 41%yield) LC/MS m/z=531 (M+Na)⁺, 1.75 min (ret.time).

tert-Butyl 3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2-methylhept-6-ynoate

To a solution of tert-butyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2-methyl-7-(trimethylsilyl)hept-6-ynoate(0.628 g, 1.234 mmol) in methanol (6.17 mL) was added K₂CO₃ (0.853 g,6.17 mmol) and the reaction stirred at ambient temperature for 2 hours.The reaction was diluted with water and extracted 3× with DCM. Combinedorganics were washed with water, brine and dried with MgSO₄. The residuewas purified by flash chromatography eluting with 0-10% EtOAc/hexane toprovide the title compound as a mixture of diasteriomers. (0.313 g, 55%yield) LC/MS m/z=459 (M+Na)⁺, 1.51, 1.54 min (ret.time).

tert-Butyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2-methylpentanoate

To a solution of tert-butyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2-methylhept-6-ynoate(0.331 g, 0.758 mmol) in tert-butanol (2.00 mL) and water (1.50 mL) in a10 mL microwave reaction vessel was added iodoethane (0.153 mL, 1.895mmol), copper(I) iodide (0.022 g, 0.114 mmol), sodium azide (0.123 g,1.895 mmol), and DIEA (0.026 mL, 0.152 mmol). The mixture was heated viamicrowave at 70° C. for 1 h. The reaction was diluted with water andEtOAc and the layers were separated. The aqueous layer was extractedwith 2×EtOAc. The combined organics were washed with water and brine anddried with MgSO₄. The residue was purified by flash chromatographyeluting with 0-70% EtOAc/hexane to provide the title compound as amixture of diasteriomers. (0.270 g, 70% yield) LC/MS m/z=508 (M+H)⁺,1.34, 1.38 min (ret. time)

tert-Butyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate

To a solution of tert-butyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2-methylpentanoate(0.270 g, 0.532 mmol) in dichloromethane (DCM) (10.00 mL) and water(1.00 mL) was added DDQ (0.145 g, 0.638 mmol). The mixture was stirredat ambient temperature for 3 h. The solvent was removed and the residuewas purified by flash chromatography eluting with 0-5% MeOH/DCM toprovide the title compound as a mixture of stereoisomers. Thestereoisomeric mixture was separated by reverse phase preparative HPLCunder neutral conditions to provide the title compound as a mixture ofenantionmers. (0.124 g, 60% yield) LC/MS m/z=388 (M+H)⁺, 1.01 min (ret.time)

tert-Butyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoate

To a solution of tert-butyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate(0.062 g, 0.160 mmol) in dichloromethane (DCM) (3 mL) was added thionylchloride (0.023 mL, 0.320 mmol) and the reaction stirred at ambienttemperature for 30 min. The solvent was removed and the residue wasdissolved in acetonitrile (4 mL). To this solution was added(R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine, hydrochloride(0.041 g, 0.192 mmol) and DIEA (0.112 mL, 0.640 mmol) The reaction washeated via microwave to 120° C. for 1 h. The solvent was removed and theresidue was purified by flash chromatography eluting with 0-40% (3:1EtOAc:EtOH)/hexane to provide the title compound. (0.068 g, 78% yield)LC/MS m/z=548 (M+H)⁺, 1.02 min (ret. time).

5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoicacid, 0.20 formic acid salt

A solution of tert-butyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoate(0.065 g, 0.114 mmol) in formic acid (1.00 mL, 22.94 mmol) was stirredat ambient temperature for 1 hour and the reaction heated to 50° C. for8 h. The reaction was then stirred at ambient temperature for 14 h. Thereaction was concentrated and the residue was purified by reverse phasepreparative HPLC using formic acid as a solvent modifier to provide thetitle compound. (0.039 g, 69% yield) LC/MS m/z=492 (M+H)⁺, 0.80 min(ret. time).

Example 2255-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2-methylpentanoicacid, Trifluoroacetic acid salt (Compound 9, Isomer 1, Scheme A)

(E)-Benzyl hept-2-en-6-ynoate

To a solution of3-((2-(dimethoxyphosphoryl)acetoxy)methyl)benzene-1-ylium (51.7 g, 201mmol) in tetrahydrofuran (THF) (150 mL) was added dium hydride (8.04 g,201 mmol)) in small portion at 0° C. After it was stirred for 35 min at0° C., pent-4-ynal (15.0 g, 183 mmol) was added slowly. The reactionmixture was sitrred at 0° C. for 50 min. Then 100 mL of saturted NH₄Clwas added and the solution was extracted with DCM (2×). The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentrated.The residue was purified by silica gel chromatography (ethylacetate:petroleum ether=1:50) to give the title compound (E)-benzylhept-2-en-6-ynoate (12.0 g, 56.0 mmol, 30.7% yield) as an oil. LC/MS m/z215.1 (M+H)⁺, 2.00 min (ret. time)

(E)-Benzyl 5-(1-ethyl-1H-1,2,3-triazol-4-yl)pent-2-enoate

To a solution of (E)-benzyl hept-2-en-6-ynoate (10.0 g, 46.7 mmol) intetrahydrofuran (THF) (200.0 mL) and water (200.0 mL) was added sodiumazide (9.10 g, 140 mmol), iodoethane (21.84 g, 140 mmol), copper(I)iodide (1.778 g, 9.33 mmol) and NaHCO₃ (11.76 g, 140 mmol) slowly undernitrogen. The reaction mixture was stirred at 70° C. for 16 h. Therection mixture was extracted with ethyl acetate (3×). The organic layerwas concentrated and the residue was purified by silica gelchromatography (ethyl acetate:petroleum ether=1:10) to give the titlecompound (E)-benzyl 5-(1-ethyl-1H-1,2,3-triazol-4-yl)pent-2-enoate (7.5g, 24.97 mmol, 53.5% yield). LC/MS m/z 286.2 (M+H)⁺, 1.78 min (ret.time)

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)pentanoate(Compound (±)-1, Scheme A)

To a solution of (E)-benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)pent-2-enoate (3.0 g, 10.51 mmol) in1,4-Dioxane (28 mL) and water (11.20 mL) was added(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(3.91 g, 15.77 mmol), [Rh(COD)Cl]₂ (0.518 g, 1.051 mmol), andtriethylamine (4.37 mL, 31.5 mmol). A stream of argon was passed throughthe mixture for 5 min and then the reaction was heated under Ar at 90°C. for 1.5 h. The reaction mixture was cooled and filtered through a padof celite, and diluted with EtOAc and water. The layers were separatedand the aqueous layer was extracted with 3× EtOAc. The combined organiclayers were concentrated and the residue was purified by flashchromatography eluting with 0-40% (3:1 EtOAc:EtOH)/hexane to provide thetitle compound. (2.66 g, 62% yield) LC/MS m/z=408 (M+H)⁺, 1.05 min (ret.time).

Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate(Compound (±)-2, Scheme A)

To a solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)pentanoate(Compound 1, Scheme A) (2.65 g, 6.50 mmol) in N,N-dimethylformamide(DMF) (25 mL) at 0° C. was added imidazole (2.214 g, 32.5 mmol) followedby tert-butyldimethylchlorosilane (2.94 g, 19.51 mmol). The reaction wasallowed to stir for 2 h while slowly warming from 0° C. to ambienttemperature. The reaction was poured over ice water and extracted withDCM. The combined organic layers were washed with water andconcentrated. The residue was purified by flash chromatography elutingwith 0-100% EtOAc/hexane to provide the title compound. (3.23 g, 95%yield) LC/MS m/z=522 (M+H)⁺, 1.54 min (ret. time).

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)pentanoate(Compound 3A, Scheme A)

To a solution of benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate(Compound 2, Scheme A) (3.45 g, 6.61 mmol) in tetrahydrofuran (THF) (30mL) was added TBAF (13.22 mL, 13.22 mmol). The reaction mixture wasallowed to stir for 20 h. The reaction was then diluted with EtOAc andwashed with 2× water and saturated NaCl. The organic layer wasconcentrated and the residue was purified by flash chromatographyeluting with 0-90% (3:1 EtOAc:EtOH)/hexane to provide 3.23 g of amixture of stereoisomers of the title compound. This compound wascombined with another batch of the same compound prepared by a methodsimilar to the one described here. The combined material was purified bychiral SFC chromatography (Column: Chiralpak AY 20×250 mm; Co-solvent:25% EtOH; Flowrate: 50 mg/min; Back pressure: 100 Bar) to yield the pureenantiomers of title compounds with unknown absolute configuration.(Compound 3A, Scheme A) (1.48 g) (chiral SFC ret. time: 3.82 min) LC/MSm/z=408 (M+H)⁺, 1.02 min (ret. time). (Compound 3B, Scheme A) (1.51 g)(chiral SFC ret. time: 5.63 min) LC/MS m/z=408 (M+H)+, 1.01 min (ret.time).

Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate(Compound 4A, Scheme A)

To a solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)pentanoate(Compound 3A, Scheme A) (1.484 g, 3.64 mmol) in N,N-dimethylformamide(DMF) (20 mL) at 0° C. was added imidazole (1.240 g, 18.21 mmol)followed by tert-butyldimethylchlorosilane (1.647 g, 10.93 mmol). Thereaction was allowed to stir for 4 h while warming from 0° C. to ambienttemperature slowly. The reaction was poured over ice water and extractedwith DCM. The combined organic layers were washed with water andconcentrated. The residue was purified by flash chromatography elutingwith 0-100% EtOAc/hexane to provide the title compound. (1.55 g, 82%yield) LC/MS m/z=522 (M+H)⁺, 1.60 min (ret. time).

Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoate(Compound 5A, Isomers 1 and 2, Scheme A)

To a solution of benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate(Compound 4A, Scheme A) (1.031 g, 1.976 mmol) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.238 mL, 1.976mmol) in tetrahydrofuran (THF) (20 mL) at −78° C. under argon was added1M LiHMDS (4.94 mL, 4.94 mmol) and the reaction allowed to stir for 50min. To the reaction mixture was added 2M methyl iodide (6.92 mL, 13.83mmol) and the reaction mixture was allowed to stir for 25 min at −78° C.before quenching with MeOH and water. The crude product was extractedwith DCM and the combined organic layers were concentrated under reducedpressure. The residue was purified by flash chromatography eluting with0-70% EtOAc/hexane to provide the title compound as a mixture ofisomers. (0.810 g, 77% yield) LC/MS m/z=536 (M+H)⁺, 1.65, 1.69 min (ret.time).

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate(Compound 6A, Isomers 1 and 2, Scheme A)

To a solution of benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoate(Compound 5A, Isomers 1 and 2, Scheme A) (0.810 g, 1.512 mmol) intetrahydrofuran (THF) (15 mL) was added TBAF (3.02 mL, 3.02 mmol). Thereaction mixture was stirred for 21 h. The reaction was then dilutedwith EtOAc and washed with 2× water and saturated NaCl. Organic layerconcentrated and the residue was purified by flash chromatographyeluting with 0-90% (3:1 EtOAc:EtOH)/hexane to provide the title compoundas a mixture of diasteriomers. (0.490 g, 77% yield) LC/MS m/z=422(M+H)⁺, 1.06, 1.08 min (ret. time).

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2-methylpentanoate(Compound 7A, Isomers 1 and 2, Scheme A)

To a solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate(Compound 6A, Isomers 1 and 2, Scheme A) (266 mg, 0.631 mmol) indichloromethane (DCM) (3 mL), was added DIEA (0.331 mL, 1.893 mmol)followed by the addition of SOCl₂ (0.092 mL, 1.262 mmol) and stirred for1.5 h at 0° C. The solvent was removed and the residue was redissolvedin N,N-dimethylformamide (DMF) (3.00 mL). To the reaction mixture wasadded 1-((1H-imidazol-2-yl)methyl)-4-ethylpiperidine, trifluoroaceticacid salt (388 mg, 1.262 mmol) and the reaction heated in microwave at120° C. for 1 h 45 min. The reaction was diluted with water andextracted with DCM. The organic layers were combined and concentratedunder reduced pressure. and the residue was purified by flashchromatography eluting with 0-100% (3:1 EtOAc:EtOH)/hexane to providethe title compound. as a crude mixture with DMF. LC/MS m/z=597 (M+H)⁺,1.10 min (ret. time). The compound was carried on to next step withoutfurther purification.

5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2-methylpentanoicacid, Trifluoroacetic acid salt (Compound 8A, Isomer 1, Scheme A)

The mixture of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2-methylpentanoate(Compound 7, Isomers 1 and 2, Scheme A) (120 mg, 0.099 mmol), and 5%Pd—C (105 mg, 0.049 mmol) in methanol (30 mL) was hydrogenated at roomatmosphere for 5 h. The reaction was filtered and the solvent wasremoved. The residue was dissolved in methanol and was subjected to H₂on an H-cube for 2 h at 25° C. using a 10% Pd—C cartridge and a flowrate of 1 mL/min. Afterwards a solution of lithium hydroxide (35.4 mg,1.478 mmol) in water (5 mL) was added to the solution in methanol (30mL). This reaction mixture was allowed to stir for 48 h at ambienttemperature. The reaction was concentrated and the residue was purifiedby reverse phase preparative HPLC using TFA as a solvent modifier toprovide the two enantiomericly pure title compounds. (Compound 8A,Isomer 1, Scheme A): (0.038 g, 62% yield) LC/MS m/z 507 (M+H)⁺, 0.86 min(ret. time). (Compound 8A, Isomer 2, Scheme A): (0.006 g, 10% yield)LC/MS m/z=507 (M+H)+, 0.84 min (ret. time)

Example 2265-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2-methylpentanoicacid, Trifluoroacetic acid salt (Compound 8B, Isomers 1 and 2, Scheme B)

Benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate(Compound 4B, Isomer 2, Scheme A)

To a solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)pentanoate(Compound 3B, Scheme A) (1.511 g, 3.71 mmol) in N,N-dimethylformamide(DMF) (20 mL) at 0° C. was added imidazole (1.262 g, 18.54 mmol)followed by tert-butyldimethylchlorosilane (1.677 g, 11.12 mmol). Thereaction was allowed to stir for 4 h while warming from 0° C. to ambienttemperature slowly. The reaction was poured over ice water and extractedwith DCM. The combined organic layers were washed with water beforebeing concentrated. The residue was purified by flash chromatographyeluting with 0-100% EtOAc/hexane to provide the title compound. (1.418g, 73% yield) LC/MS m/z=522 (M+H)⁺, 1.63 min (ret. time).

Mixture of benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoate(Compound 5B, Isomers 1 and 2, Scheme B) and methyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoate(Compound 9B, Isomers 1 and 2, Scheme B)

To a solution of benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate(Compound 4B, Scheme B) (1.5 g, 2.87 mmol) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.347 mL, 2.87 mmol)in tetrahydrofuran (THF) (20 mL) at −78° C. under argon was added 1MLiHMDS (7.19 mL, 7.19 mmol) and the reaction allowed to stir for 50 min.To the reaction mixture was added 2M methyl iodide (10.06 mL, 20.12mmol) and the reaction mixture was allowed to stir for 25 min at −78° C.before quenching with MeOH. The reaction was concentrated and theresidue was purified by flash chromatography eluting with 0-100%EtOAc/hexane to provide a crude mixture containing the title compounds.This crude material was re-purified by flash chromatography eluting with0-55% EtOAc/hexane to provide a mixture of the title compounds (0.901 g)This mixture was carried on without further purification. LC/MS [Benzylester (Compound 5B, Isomers 1 and 2, Scheme B)] m/z 536.3 [M+H]⁺, 1.68min (ret. time). [Methyl ester (Compound 9B, Isomers 1 and 2, Scheme B)]m/z=460.3 (M+H)⁺, 1.48 min and 1.53 min (ret. time)

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate(Compound 6B, Isomers 1 and 2, Scheme B)

Methyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate(Compound 13B, Isomers 1 and 2, Scheme D)

A mixture of benzyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoate(Compound 5B, Isomers 1 and 2, Scheme B) and methyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoate(Compound 9B, Isomers 1 and 2, Scheme B) (901 mg) were dissolved intetrahydrofuran (THF) (15 mL) followed by addition of TBAF (1.196 mL,1.196 mmol). The reaction mixture was allowed to stir for 19 h. Thesolvent was removed under reduced pressure. The residue was dissolved inEtOAc and washed with 2× water and saturated NaCl. The organic layer wasconcentrated and the residue was purified by reverse phase preparativeHPLC under neutral conditions to provide benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate(Compound 6B, Isomers 1 and 2, Scheme B) (0.091 g) LC/MS m/z 422 (M+H)+,1.06 min (ret. time), and methyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate(Compound 13B, Isomers 1 and 2, Scheme D) (0.459 g) LC/MS m/z=346(M+H)+, 0.78 min and 0.82 min (ret. time)

Benzyl3-(3-(chloromethyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoate(Compound 10B, Isomers 1 and 2, Scheme B)

To a solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate(Compound 6B, Isomers 1 and 2, Scheme B) (95 mg, 0.225 mmol) indichloromethane (DCM) (3 mL), was added DIEA (0.118 mL, 0.676 mmol)followed by the addition of SOCl₂ (0.033 mL, 0.451 mmol) and stirred for1.5 h in an ice-water bath. The solvent was removed and the residue waspurified by flash chromatography eluting with 0-10% MeOH/DCM to providethe title compound as a crude mixture. This mixture was carried onwithout further purification. (0.079 g) LC/MS m/z=440 (M+H)⁺, 1.30 min(ret. time).

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2-methylpentanoate(Compound 7B, Isomers 1 and 2, Scheme B)

To a solution of 1-((1H-imidazol-2-yl)methyl)-4-ethylpiperidine,trifluoroacetic acid salt (110 mg, 0.359 mmol) in N,N-dimethylformamide(DMF) (3 mL) was added 1M LiHMDS (0.539 mL, 0.539 mmol) and the reactionallowed to stir for 30 min at 0° C. To this reaction mixture was addedbenzyl3-(3-(chloromethyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoate(Compound 10B, Isomers 1 and 2, Scheme B) (79 mg, 0.180 mmol). Thisreaction mixture was allowed to stir for 1 h. To the reaction mixture at0° C. was added another portion of LiHMDS (0.539 mL, 0.539 mmol). Thisreaction mixture was allowed to stir for an additional 1 h. To thereaction mixture, at ambient temperature, was added another portion ofLiHMDS (0.539 mL, 0.539 mmol). This reaction mixture was allowed to stirfor an additional 1 h. The reaction was quenched with saturated aqueousammonium chloride, diluted with water and extracted with DCM. Theorganic layers were combined and concentrated under reduced pressure andthe residue was purified by flash chromatography eluting with 0-100%(3:1 EtOAc:EtOH)/hexane to provide the title compound. (0.045 g, 42%yield) LC/MS m/z=597 (M+H)⁺, 1.10 min (ret. time).

(2S,3R)-5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2-methylpentanoicacid, Trifluoroacetic acid salt (Compound 8B, Isomers 1 and 2, Scheme B)

A solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2-methylpentanoate(Compound 16, Isomers 1 and 2, Scheme A) (45 mg, 0.037 mmol), inmethanol (10 mL) was hydrogenated in H-cube for 2 h at 40° C. using a10% Pd—C cartridge and a flow rate of 1 mL/min. The solvent was removedand the residue was purified by reverse phase preparative HPLC using TFAas a solvent modifier to provide the title compound as a mixture ofisomers. (0.028 g) LC/MS m/z=507 (M+H)⁺, 0.76 min (ret. time).

Example 2273-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoicacid, Trifluoroacetic acid salt (Compound 12B, Isomers 1 and 2, SchemeD)

Methyl3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoate(Compound 14B, Isomers 1 and 2, Scheme D)

To a solution of methyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate(Compound 13B, Isomers 1 and 2, Scheme B) (202 mg, 0.585 mmol) indichloromethane (DCM) (3 mL), was added DIEA (0.306 mL, 1.754 mmol)followed by the addition of SOCl₂ (0.085 mL, 1.170 mmol). This reactionmixture was allowed to stir for 1.5 h in an ice-water bath. The solventwas removed and and redissolved in N,N-dimethylformamide (DMF) (3.00mL). To the reaction mixture was added2,2-dimethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine hydrochloride(251 mg, 1.170 mmol) and the reaction heated in microwave at 120° C. for1 h. The reaction was diluted with water and extracted with DCM. Theorganic layers were combined and concentrated under reduced pressure.The residue was purified by flash chromatography eluting with 0-80% (3:1EtOAc:EtOH)/hexane to provide the title compound the title compound. asa crude mixture with DMF (0.314 g) LC/MS m/z=506 (M+H)⁺, 0.91 min and0.93 min (ret. time). The compound was carried on to next step withoutfurther purification.

(2S,3R)-3-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoicacid, Trifluoroacetic acid salt (Compound 12B, Isomers 1 and 2, SchemeD)

To a solution of methyl3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoate(Compound 14B, Isomers 1 and 2, Scheme D) (310 mg, 0.613 mmol) intetrahydrofuran (THF) (6 mL) was added a solution of LiOH (147 mg, 6.13mmol) in water (2 mL), followed by the addition of methanol (1 mL). Thereaction was allowed to stir at ambient temperature for 19 h. Thesolvents were evaporated and the aqueous layer was acidified beforeextracting with DCM. The solvent was removed and the residue waspurified by reverse phase preparative HPLC using TFA as a solventmodifier to provide the title compound as a mixture of isomers. (0.094g, 25% yield) LC/MS m/z=492 (M+H)⁺, 0.80 min (ret. time).

Example 2283-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoicacid (Compound 12A, Isomers 1 and 2, Scheme C)

Benzyl3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoate(Compound 11, Isomers 1 and 2, Scheme C)

To a solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methylpentanoate(Compound 6A, Isomers 1 and 2, Scheme C) (159 mg, 0.377 mmol) indichloromethane (DCM) (3 mL), was added DIEA (0.198 mL, 1.132 mmol)followed by the addition of SOCl₂ (0.055 mL, 0.754 mmol). This reactionmixture was allowed to stir for 1.5 h in an ice-water bath. The solventwas removed and the residue was redissolved in N,N-dimethylformamide(DMF) (3.00 mL). To the reaction mixture was added2,2-dimethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine hydrochloride(162 mg, 0.754 mmol) and the reaction heated in microwave 0 at 120° C.for 1 h. The reaction was diluted with water and extracted with DCM. Theorganic layers were combined and concentrated under reduced pressure.The residue was purified by flash chromatography eluting with 0-90% (3:1EtOAc:EtOH)/hexane to provide the title compound the title compound. asa crude mixture with DMF (0.245 g) LC/MS m/z=582 (M+H)+, 1.00 min. Thecompound was carried on to next step without further purification.

3-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoicacid (Compound 12A, Isomers 1 and 2, Scheme C)

A solution of benzyl3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoate(Compound 11A, Isomers 1 and 2, Scheme C) (245 mg, 0.379 mmol) inmethanol (15 mL) was hydrogenated in H-cube for 2 h at 30° C. and 20 bar(pressure) using a 10% Pd—C cartridge and a flow rate of 1 mL/min. Thesolvent was removed and the residue was purified by reverse phasepreparative HPLC using TFA as a solvent modifier to provide the titlecompound. (0.028 g, 15% yield) LC/MS m/z=492 (M+H)⁺, 0.89 min (ret.time).

Example 229 Benzyl3-(4-chloro-3-((2-(cycloheptylmethyl)-1H-imidazol-1-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoate

(5-Bromo-2-chlorophenyl)methanol

A solution of 5-bromo-2-chlorobenzoic acid (5 g, 21.23 mmol) wasdissolved in tetrahydrofuran (THF) (10 mL) at 0° C., then 10Mborane-methyl sulfide complex (1.062 mL, 10.62 mmol) was added to thereaction mixture The reaction was warmed to 23° C. and stirred for 14 h.The reaction was cooled on an ice water bath and methanol (2.00 mL) wasadded slowly. When most of the gas evolution ended the volatile solventswere removed in vacuo. The residue was dissolved in EtOAc (10 mL) andwashed with saturated aqueous NaHCO₃. The aqueous layer was extractedagain with EtOAc (50 mL) and the combined EtOAc was washed with water (5mL), saturated aqueous NaCl, dried with Na₂SO₄ and concentrated toprovide the title product. (4.624 g, 20.88 mmol, 98% yield) LC/MSm/z=219 (M+H)⁺, 0.79 min (ret. time).

4-Bromo-1-chloro-2-(((4-methoxybenzyl)oxy)methyl)benzene

5-bromo-2-chlorophenyl)methanol (5.361 g, 24.21 mmol) was dissolved inN,N-dimethylformamide (DMF) (40 mL) under argon and cooled in anice-bath at 0° C. 60% sodium hydride (1.936 g, 48.4 mmol) was addedcarefully in several portions. The reaction was stirred at 23° C. for 1h then cooled to 10° C., and 1-(chloromethyl)-4-methoxybenzene (4.92 mL,36.3 mmol) was added. The reaction was stirred at 23° C. for 14 h. Thereaction was carefully quenched with water (25 mL) and stirred for 5min. The reaction was diluted with water (100 mL) and EtOAc (300 mL).The layers were separated and the product was extracted with additionalEtOAc (2×200 mL). The combined organics were washed with water (4×100mL), saturated aqueous NaCl (2×100 mL), and dried with Na₂SO₄. Thesolvent was concentrated and the residue was purified by flashchromatography eluting with 0-100% acetone/hexanes to provide the titlecompound (5.81 g, 15.48 mmol, 63.9% yield) LC/MS m/z=339 (M+H)+, 1.40min. (ret. time).

5-(Trimethylsilyl)pent-4-ynal

5-(Trimethylsilyl)pent-4-yn-1-ol (6.81 mL, 37.5 mmol) was dissolved indichloromethane (DCM) (30 mL) and was added portion wise into a solutionof Dess-Martin periodinane (19.54 g, 46.1 mmol) in DCM (30 mL) at 0° C.The reaction was diluted with additional dichloromethane (DCM) (10.0 mL)and stirred at ambient temperature for 1 h. The reaction was quenchedwith sodium thiosulfate (10 g) solution containing NaHCO₃. The aqueouslayer was washed with DCM (30 mL). The organic layers were combined,dried over Na₂SO₄, and evaporated. The solvent was concentrated and theresidue was purified by flash chromatography eluting with 0-25%acetone/hexanes to provide the title compound (4.78 g, 31.0 mmol, 83%yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.14 (s, 9H) 2.50-2.57 (m,2H) 2.63-2.70 (m, 2H) 9.79 (s, 1H)

1-(4-Chloro-3-(((4-methoxybenzyl)oxy)methyl)phenyl)-5-(trimethylsilyl)pent-4-yn-1-ol

5-(Trimethylsilyl)pent-4-ynal (4.22 g, 27.4 mmol) was dissolved in drytetrahydrofuran (THF) (81 mL), and stirred with activated molecularsieves for 2 h. In a separate flask,4-bromo-1-chloro-2-(((4-methoxybenzyl)oxy)methyl)benzene (4.45 g, 13.03mmol) was dissolved in dry tetrahydrofuran (THF) (81 mL) and stirredwith activated molecular sieves for 2 h. This solution was cooled to−78° C. and 1.6M n-butyllithium (9.77 mL, 15.63 mmol) was added to thereaction mixture. Next, 5-(trimethylsilyl)pent-4-ynal (4.22 g, 27.4mmol) in THF was added slowly and the reaction was stirred in at −78° C.for 2 h. The reaction was diluted with water (25 mL) and EtOAc (75 mL).The aqueous layer was extracted with an additional portion of EtOAc (50mL) and the combined organics were washed with water (50 mL), saturatedaqueous NaCl (50 mL) and dried with Na₂SO₄. The solvent was concentratedand the residue was purified by reverse phase preparative HPLC underneutral conditions to provide the title compound (1 g, 2.398 mmol,18.41% yield). ¹H NMR (400 MHz, CHLOROFORM-d) d ppm 0.11-0.25 (m, 9H)2.79 (s, 1H) 3.84 (s, 4H) 4.61 (s, 2H) 4.65 (s, 2H) 4.88 (dd, J=7.53,5.02 Hz, 1H) 6.93 (d, J=8.03 Hz, 3H) 7.24 (d, J=2.01 Hz, 1H) 7.32-7.39(m, 3H) 7.52 (s, 1H)

(5-Bromo-5-(4-chloro-3-(((4-methoxybenzyl)oxy)methyl)phenyl)pent-1-yn-1-yl)trimethylsilane

1-(4-Chloro-3-(((4-methoxybenzyl)oxy)methyl)phenyl)-5-(trimethylsilyl)pent-4-yn-1-ol(1 g, 2.398 mmol) was dissolved in dichloromethane (DCM) (48.0 mL).Triphenylphosphine (polymer bound, 2.26 mmol/g) (3.18 g, 7.19 mmol) wasadded with perbromomethane (0.954 g, 2.88 mmol) and allowed to stir atambient temperature for 1 h. The solvent was concentrated and theresidue was purified by flash chromatography eluting with 0-25%acetone/hexanes to provide the title compound (0.830 g, 1.729 mmol,72.1% yield). LC/MS m/z=479 (M+H)⁺, 1.76 min (ret. time).

Benzyl3-(4-chloro-3-(((4-methoxybenzyl)oxy)methyl)phenyl)-2,2-dimethyl-7-(trimethylsilyl)hept-6-ynoate

Diisopropylamine (2.424 mL, 17.29 mmol) was dissolved in tetrahydrofuran(THF) (25.8 mL) and cooled to −70° C. The reaction mixture was treatedwith 1.6M n-butyllithium (in hexanes) (6.49 mL, 10.38 mmol) and stirredat −70° C. for 15 min, warmed to 0° C. for 15 min, and then re-cooled to−70° C. Benzyl isobutyrate (1.967 mL, 11.07 mmol) in tetrahydrofuran(THF) (25.8 mL) was added to the reaction dropwise and was stirred at−70° C. for 45 min, warmed to −50° C. for 15 min and recooled to −70° C.(5-bromo-5-(4-chloro-3-(((4-methoxybenzyl)oxy)methyl)phenyl)pent-1-yn-1-yl)trimethylsilane(0.830 g, 1.729 mmol), dissolved in tetrahydrofuran (THF) (25.8 mL), wasadded dropwise to the reaction followed by dry1,3-dimethyltetrahydropyrimidin-2(1H)-one (4.18 mL, 34.6 mmol). Thereaction was stirred for 1 h at −70° C. and then warmed to −45° C. Thereaction was diluted with EtOAc (30 mL) and the aqueous phases wereextracted with EtOAc (2×). The combined organics were washed with water,saturated aqueous NaCl, and dried with Na₂SO₄. The solvent wasconcentrated and the residue was purified by flash chromatographyeluting with 0-30% acetone/hexanes to provide the title compound (600mg, 1.039 mmol, 60.1% yield). LC/MS m/z=578 (M+H)⁺, 1.83 min (ret.time).

Benzyl3-(4-chloro-3-(((4-methoxybenzyl)oxy)methyl)phenyl)-2,2-dimethylhept-6-ynoate

Benzyl3-(4-chloro-3-(((4-methoxybenzyl)oxy)methyl)phenyl)-2,2-dimethyl-7-(trimethylsilyl)hept-6-ynoate(600 mg, 1.039 mmol) was dissolved in methanol (5.547 mL). Potassiumcarbonate (718 mg, 5.20 mmol) was added and stirred for 2 h. Afterwards,the solvent was condensed, and the residual oil was diluted with water,and extracted with DCM (3×). The organic layers were dried with MgSO₄,and the solvents were removed in vacuo to afford the title compound (400mg, 0.792 mmol, 76% yield). LC/MS m/z=527 (M+H)⁺, 1.56 min (ret. time).

Benzyl3-(4-chloro-3-(((4-methoxybenzyl)oxy)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoate

Sodium azide (129 mg, 1.980 mmol), iodoethane (146 μl, 1.822 mmol),copper(I) iodide (22.63 mg, 0.119 mmol), and Hunig's base (27.7 μl,0.158 mmol) were added to a solution of benzyl3-(4-chloro-3-(((4-methoxybenzyl)oxy)methyl)phenyl)-2,2-dimethylhept-6-ynoate(400 mg, 0.792 mmol) in tert-butanol (1.9 mL)) and water (1.9 mL) andthen heated via microwave at 70° C. for 1 h. The reaction was cooled,diluted with EtOAc (150 mL) and water (50 mL). The aqueous portion wasextracted again with EtOAc (75 mL) and the combined organics were washedwith water (50 mL), saturated aqueous NaCl (25 mL), and dried withNa₂SO₄. The solvent was concentrated and the residue was purified byflash chromatography eluting with 0-70% acetone/hexanes to provide thetitle compound (400 mg, 0.597 mmol, 75% yield). LC/MS m/z=576 (M+H)⁺,1.48 min (ret. time).

Benzyl3-(4-chloro-3-(hydroxymethyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoate

Benzyl3-(4-chloro-3-(((4-methoxybenzyl)oxy)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoate(810 mg, 1.406 mmol) was dissolved in acetonitrile (6.5 mL) and wascombined with ceric ammonium nitrate (2312 mg, 4.22 mmol) and water(0.725 mL) and stirred 1 h. The reaction was diluted with EtOAc (100 mL)and water (50 mL), and the phases were separated. The aqueous phase wasextracted again with EtOAc (50 mL) and the combined organics were washedwith water (50 mL), saturated aqueous NaCl and dried with Na₂SO₄. Thesolvent was concentrated and the residue was purified by flashchromatography eluting with 0-30% acetone/hexanes to provide the titlecompound (510 mg, 1.051 mmol, 74.8% yield). LC/MS m/z=456 (M+H)⁺, 1.11min (ret. time)

Benzyl3-(4-chloro-3-((2-(cycloheptylmethyl)-1H-imidazol-1-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoate

To a solution of benzyl3-(4-chloro-3-(hydroxymethyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoate(40 mg, 0.088 mmol) in dichloromethane (DCM) (6 mL) was added thionylchloride (0.016 mL, 0.219 mmol) and stirred at ambient temperature for30 min. The solvent was removed and the residue was dissolved inacetonitrile (6.00 mL). DIEA (0.115 mL, 0.658 mmol) and2-(cycloheptylmethyl)-1H-imidazole (39 mg, 0.219 mmol) were then addedand the reaction was heated via microwave to 120° C. for 2.5 h. Thesolvent was then concentrated and the residue was purified by reversephase preparative HPLC under neutral conditions to provide the titlecompound. (45 mg, 0.073 mmol, 83% yield) LC/MS m/z=616 (M+H)⁺, 1.2 min(ret. time).

Benzyl3-(4-chloro-3-((2-(cycloheptylmethyl)-1H-imidazol-1-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoate

Benzyl3-(4-chloro-3-((2-(cycloheptylmethyl)-1H-imidazol-1-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoate(40 mg, 0.065 mmol) was dissolved in tetrahydrofuran (THF) (2.000 mL),water (1.000 mL) and methanol (2 mL) in a 2.5 mL Biotage microwavereaction vessel. Lithium hydroxide (7.77 mg, 0.325 mmol) was added andthe reaction mixture was heated via microwave at 100° C. for 2 h. Thereaction was made acidic using 10% formic acid. The solvent wasconcentrated and the residue was purified by reverse phase preparativeHPLC using formic acid as a solvent modifier to provide the titlecompound (12 mg, 0.022 mmol, 34.4% yield). LC/MS m/z=575 (M+H)⁺, 0.93min (ret. time).

Example 2303-(4-Chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoicacid

Benzyl3-(4-chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoate

To a solution of benzyl3-(4-chloro-3-(hydroxymethyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoate(85 mg, 0.186 mmol) in dichloromethane (DCM) (6 mL) was added thionylchloride (0.016 mL, 0.219 mmol). The resulting reaction solution wasstirred at ambient temperature for 30 min. The solvent was removed andthe residue was dissolved in acetonitrile (6.00 mL) and DIEA (0.160 mL,0.916 mmol) and 1-((1H-imidazol-2-yl)methyl)-4-ethylpiperidine (48.0 mg,0.248 mmol) was added. The reaction was heated via microwave to 120° C.for 2 h. The solvent was concentrated and the residue was purified byreverse phase preparative HPLC using formic acid as a solvent modifierto provide the title compound (112 mg, 0.177 mmol, 95% yield). LC/MSm/z=631 (M+H)⁺, 1.09 min (ret. time).

3-(4-Chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoicacid

Benzyl3-(4-chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoate(112 mg, 0.177 mmol) was dissolved in tetrahydrofuran (THF) (1.000 mL),water (1.000 mL) and MeOH (2 mL). Lithium hydroxide (21.25 mg, 0.887mmol) was added to the reaction mixture and the mixture heated viamicrowave at 100° C. for 1 h. The reaction was quenched using 10% formicacid. The solvent was concentrated and the residue was purified byreverse phase preparative HPLC using formic acid as a solvent modifierto provide the title compound (13 mg, 0.024 mmol, 13.54%). LC/MS m/z=541(M+H)⁺, 0.86 min (ret. time).

Example 2313-(4-Chloro-3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoicacid

Benzyl3-(4-chloro-3-(hydroxymethyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate

(E)-Benzyl 5-(1-ethyl-1H-1,2,3-triazol-4-yl)pent-2-enoate (0.5 g, 1.752mmol),(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(1.035 g, 3.86 mmol), and chloro(1,5-cyclooctadiene)rhodium(I) dimer(0.086 g, 0.175 mmol) were all dissolved in 1,4-dioxane (10.00 mL) andwater (5 mL). The mixture was degassed with argon, afterwhich,triethylamine (1.465 mL, 10.51 mmol) was added. The reaction mixture washeated to 90° C. and stirred overnight. Additional(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(1.035 g, 3.86 mmol), chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.086g, 0.175 mmol) and triethylamine (1.465 mL, 10.51 mmol) were then addedand heating was continued at 90° C. for 3 h. The solvent wasconcentrated and the residue was purified by flash chromatographyeluting with 0-90% acetone/hexanes to provide the title compound. (40mg, 0.080 mol, 4.59% yield) LC/MS m/z=427 (M+H)⁺, 1.05 min (ret. time).

Benzyl3-(4-chloro-3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate

To a solution of benzyl3-(4-chloro-3-(hydroxymethyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate(0.080 g, 0.187 mmol) in dichloromethane (DCM) (6 mL) was added thionylchloride (0.027 mL, 0.374 mmol) and stirred at ambient temperature for30 min. The solvent was removed and the residue was dissolved inacetonitrile (10.00 mL).(R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine (0.037 g,0.206 mmol) and DIEA (0.131 mL, 0.748 mmol) were added to the solutionand the solution heated via microwave to 120° C. for 1.5 h. The solventwas concentrated and the residue was purified by flash chromatographyeluting with 0-40% acetone/hexanes to provide the title compound (0.075g, 68.2% yield). LC/MS m/z=588(M+H)⁺, 1.05 min (ret. time).

3-(4-Chloro-3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoicacid

To a solution of benzyl3-(4-chloro-3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate(75 mg, 0.128 mmol) in tetrahydrofuran (THF) (2.0 mL) and water (1 mL)was added lithium hydroxide (15.27 mg, 0.638 mmol). The resultingreaction mixture was stirred at ambient temperature for 1 h. Thereaction was acidified with 10% formic acid, the solvent wasconcentrated and the residue was purified by reverse phase preparativeHPLC using formic acid as a solvent modifier to provide the titlecompound (25 mg, 0.050 mmol, 39.4% yield). LC/MS m/z=498(M+H)⁺, 0.84 min(ret. time).

Example 2325-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)pentanoicacid

Ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)pentanoate

To a solution of ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)pentanoate(60 mg, 0.174 mmol) in dichloromethane (DCM) (6 mL) was added thionylchloride (0.025 mL, 0.347 mmol) and the resulting solution stirred atambient temperature for 30 min. The solvent was removed and the residuewas dissolved in acetonitrile (10.00 mL). To this solution was added(R)-2-ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine (49.5 mg,0.278 mmol) and DIEA (0.182 mL, 1.042 mmol). The reaction was heated viamicrowave to 120° C. for 2 h. The solvent was concentrated and theresidue was purified by flash chromatography eluting with 0-75%acetone/hexanes to provide the title compound (25 mg, 0.046 mmol, 26.5%yield). LC/MS m/z=506 (M+H)+, 0.86 min (ret. time)

5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)pentanoicacid

To a solution of ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)pentanoate(20 mg, 0.040 mmol) in tetrahydrofuran (THF) (2.000 mL) and water (1 mL)was added lithium hydroxide (4.74 mg, 0.198 mmol) and the reactionmixture stirred at ambient temperature for 1 h afterwhich timeadditional lithium hydroxide (0.947 mg, 0.040 mmol) was added to thereaction mixture. The reaction was heated via microwave to 120° C. for 2h The solvent was concentrated and the residue was purified by reversephase preparative HPLC using formic acid as a solvent modifier toprovide the title compound (1 g, 2.398 mmol, 18.41% yield).

LC/MS m/z=478 (M+H)⁺, 0.72 min (ret. time).

Example 2333-(4-Chloro-3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoicacid

Benzyl3-(4-chloro-3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate

To a solution of benzyl3-(4-chloro-3-(hydroxymethyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate(80 mg, 0.187 mmol) in dichloromethane (DCM) (5.00 mL) was added thionylchloride (0.027 mL, 0.374 mmol) and the solution stirred at ambienttemperature for 30 min. The solvent was removed and the residue wasdissolved in acetonitrile (10 mL).2,2-dimethyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (36.7 mg,0.206 mmol) and DIEA (0.033 mL, 0.187 mmol) was added to the mixture andthe reaction heated via microwave to 120° C. for 1.5 h. The solvent wasconcentrated and the residue was purified by flash chromatographyeluting with 0-40% acetone/hexanes to provide the title compound (0.043g, 35.6% yield). LC/MS m/z=588 (M+H)⁺, 1.05 min (ret. time).

3-(4-Chloro-3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoicacid

To a solution of benzyl3-(4-chloro-3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoate(75 mg, 0.128 mmol) in tetrahydrofuran (THF) (2.0 mL) and water (1 mL)was added lithium hydroxide (15.27 mg, 0.638 mmol) and stirred atambient temperature for 2 h. The reaction was acidified with 10% formicacid. The solvent was concentrated and the residue was purified byreverse phase preparative HPLC using formic acid as a solvent modifierto provide the title compound (18 mg, 0.036 mmol, 28.3% yield). LC/MSm/z=498 (M+H)⁺, 0.74 min (ret. time).

Example 2345-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-N-(methylsulfonyl)pentanamide

Ethyl5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)pentanoate

To a solution of ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)pentanoate(60 mg, 0.135 mmol) in dichloromethane (DCM) (6 mL) was added thionylchloride (0.020 mL, 0.271 mmol) and stirred at ambient temperature for30 min. The solvent was removed and the residue was dissolved inacetonitrile (10.00 mL).(R)-2-ethyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine (38.6 mg,0.217 mmol) and DIEA (0.142 mL, 0.813 mmol) were added to the reactionmixture which was heated via microwave to 120° C. for 2 h. The solventwas concentrated and the residue was purified by flash chromatographyeluting with 0-75% acetone/hexanes to provide the title compound (48 mg,0.095 mmol, 70.1% yield). LC/MS m/z=506 (M+H)+, 0.88 min (ret. time).

5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)pentanoicacid

To a solution of ethyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)pentanoate(48 mg, 0.095 mmol) in tetrahydrofuran (THF) (2.000 mL) and water (1mL), was added lithium hydroxide (11.37 mg, 0.475 mmol) and stirred atambient temperature afterwhich the reaction mixture was heated viamicrowave at 70° C. for 1 h. The solvent was concentrated and theresidue was purified by reverse phase preparative HPLC using formic acidas a solvent modifier to provide the title compound (20 mg, 0.042 mmol,44.1% yield). LC/MS m/z=478 (M+H)⁺, 0.71 min (ret. time).

5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-N-(methylsulfonyl)pentanamide

5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)pentanoicacid (20 mg, 0.042 mmol) was dissolved in dichloromethane (DCM) (2 mL)and added to a solution of EDC (24.08 mg, 0.126 mmol), DMAP (15.35 mg,0.126 mmol), TEA (0.035 mL, 0.251 mmol) in dichloromethane (DCM) (2 mL).The reaction mixture was allowed to stir for 20 min at ambienttemperature. Methanesulfonamide (19.92 mg, 0.209 mmol) was then addedand the reaction was allowed to stir for an additional 43 h at ambienttemperature. The solvent was concentrated and the residue was purifiedby reverse phase preparative HPLC using formic acid as a solventmodifier to provide the title compound (10 mg, 0.018 mmol, 43.0% yield).LC/MS m/z=555 (M+H)⁺, 0.7 min (ret. time).

Example 235(S)-3-(3-((2-(Cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

Methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(4.0 g, 10.49 mmol) in dichloromethane (DCM) (20 mL) SOCl₂ (1.531 mL,20.97 mmol) was added slowly. The reaction mixture was stirred atambient temperature for 1 h and 15 min. The solvent was evaporated toobtain the title compound methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethypropanoate(4.0 g, 95% yield) which was carried to the next step without furtherpurification. LC/MS m/z 400.0 (M+H)⁺, 1.23 (ret. time).

(S)-Methyl3-(3-((2-(cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To a solution of 2-(cycloheptylmethyl)-1H-imidazole (2.67 g, 15.00 mmol)in N,N-dimethylformamide (DMF) (10 mL), NaH (0.720 g, 30.0 mmol)methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(4.0 g, 10.00 mmol) was added slowly at ambient temperature. Thereaction mixture was stirred at ambient temperature for 16 h. Thereaction mixture was partitioned between ethyl acetate and water. Thewater layer was extracted with ethyl acetate (2×). The combined organicphase was washed with brine and dried over MgSO₄ and concentrated. Thecrude product was purified by silica gel chromatography (hexane:ethylacetate in EtOH=3:1) to obtain methyl3-(3-((2-(cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(5.2 g, 96% yield) which was separated by Chiral SFC (Column: ChiralpakAD 20×150 mm; Co-solvent: 20% MeOH:IPA (1:1); Flowrate: 50 g/min; Backpressure: 100 Bar) to obtain the title compound (S)-Methyl3-(3-((2-(cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(2.3 g, 42.4% yield) (chiral SFC ret. time: 4.32 min). LC/MS m/z 542.4(M+H)⁺, 1.03 (ret. time).

(S)-3-(3-((2-(Cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

To a solution of (S)-methyl3-(3-((2-(cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(2.3 g, 4.25 mmol) LiOH (2M, 12.74 mL, 25.5 mmol) was added. Thereaction mixture was heated via microwave at 120° C. for 2 h 15 min. Thesolvent was evaporated and the residue was partitioned between 1 N HCland ethyl acetate. The water layer was extracted with ethyl acetate(2×). The combined organic phase was dried over MgSO₄ and concentratedto get 1.930 g of the crude product which was crystallized from EtOH toobtain the title compound(S)-3-(3-((2-(cycloheptylmethyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid (1.0965 g, 48.1% yield). LC/MS m/z 528.3 (M+H)⁺, 0.91 (ret. time).

Example 2363-(4-Chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

((5-Bromo-2-chlorobenzyl)oxy)(tert-butyl)dimethylsilane

To a solution of (5-bromo-2-chlorophenyl)methanol (12 g, 54.2 mmol) indichloromethane (DCM) (150 mL), tert-butylchlorodimethylsilane (12.25 g,81 mmol) and 1H-imidazole (7.38 g, 108 mmol) were added. The reactionmixture was stirred at 0° C. to 25° C. for 2 h. The reaction mixture wasquenched with water and extracted with DCM (3×). The combined organiclayer was washed with water (2×), brine (2×), dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography(petroleum ether:ethyl acetate=1:10) to obtain the title compound((5-bromo-2-chlorobenzyl)oxy)(tert-butyl)dimethylsilane (16 g, 39.1mmol, 72.1% yield) as a colorless oil. ¹H NMR (CDCl₃, 500 MHz):7.72-7.71 (m, 1H), 7.35-7.33 (m, 1H), 7.20-7.18 (m, 1H), 4.77 (s, 2H),1.00 (s, 9H), 0.17 (s, 6H).

3-(((Tert-butyldimethylsilyl)oxy)methyl)-4-chlorobenzaldehyde

To a solution of ((5-bromo-2-chlorobenzyl)oxy)(tert-butyl)dimethylsilane(16.0 g, 47.7 mmol) in tetrahydrofuran (THF) (150 mL) was addedn-butyllithium (22.87 mL, 57.2 mmol, 2.5 M solution in THF) at −78° C.under nitrogen. After the reaction mixture was stirred at −78° C. for 30min, DMF (18.45 mL, 238 mmol) was slowly added. The reaction mixture wascontinuously stirred for 2 h at −78° C. and quenched with saturatedNH₄CL solution and extracted with ethyl acetate (3×). The combinedorganic layer was washed with water, brine, dried over anhydrous Na₂SO₄and concentrated. The residue was purified by silica gel chromatography(petroleum ether:ethyl acetate=4:1) to obtain the title compound3-(((tert-butyldimethylsilyl)oxy)methyl)-4-chlorobenzaldehyde (9.0 g,30.0 mmol, 63.0% yield) as a light yellow oil. ¹H NMR (CDCl₃, 500 MHz):10.03 (s, 1H), 8.11 (s, 1H), 7.77-7.75 (m, 1H), 7.51-7.49 (m, 1H), 4.85(s, 2H), 1.01 (s, 9H), 0.19 (s, 6H).

(3-(((Tert-butyldimethylsilyl)oxy)methyl)-4-chlorophenyl)(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol

To a solution of 5-bromo-1,4-dimethyl-1H-benzo[d][1,2,3]triazole (6 g,26.5 mmol) in tetrahydrofuran (THF) (100 mL) was added tert-butyllithium(20.42 mL, 26.5 mmol, 1.3 M solution in hexane) at −78° C. undernitrogen. After the reaction mixture was stirred at −78° C. for 30 min,3-(((tert-butyldimethylsilyl)oxy)methyl)-4-chlorobenzaldehyde (7.94 g,27.9 mmol) in tetrahydrofuran (THF) (100 mL) was added dropwise andcontinually stirred for 2 h at −78° C. The reaction mixture was slowlywarmed to ambient temperature and stirred for an additional 2 h. Thereaction mixture was quenched with saturated NH₄Cl solution andextracted with ethyl acetate (3×). The combined organic layer was washedwith brine and dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified by silica gel chromatography (petroleum ether:ethylacetate=3:1) to give the title compound(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-chlorophenyl)(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol(3.8 g, 6.42 mmol, 24.19% yield) as a light yellow oil. LC/MS m/z 432.1(M+H)⁺, 1.97 (ret. time).

Methyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-chlorophenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To a solution of(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-chlorophenyl)(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol(1.4 g, 3.24 mmol) in dry acetonitrile (30 mL) was slowly added DBU(9.77 μL, 0.065 mmol) and 2,2,2-trichloroacetonitrile (0.561 g, 3.89mmol) under nitrogen at 25° C. After the reaction mixture was stirred at25° C. for 30 min,((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (1.412 g, 8.10mmol) was added followed by1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (0.046g, 0.162 mmol). The reaction mixture was stirred at ambient temperaturefor 2 h after which 30 mL of water was added to quench the reaction. Themixture was extracted with ethyl acetate (3×). The combined organiclayer was washed with brine and concentrated. The crude product waspurified by silica gel chromatography (petroleum ether:ethylacetate=4:1) to give the title compound methyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-chlorophenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(1.2 g, 2.209 mmol, 68.2% yield) as a yellow solid. LC/MS m/z 516.1(M+H)⁺, 2.19 (ret. time).

Methyl3-(4-chloro-3-(hydroxymethyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To a solution of methyl3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-chlorophenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(2.8 g, 4.88 mmol) in tetrahydrofuran (THF) (20 mL) was added TBAF (5.86mL, 5.86 mmol) slowly under nitrogen at 25° C. The reaction mixture wasstirred at 25° C. for 16 h. Water (30 mL) was added and the reactionmixture extracted with ethyl acetate (3×). The combined organic layerwas concentrated. The crude product was purified by silica gelchromatography (hexane:ethyl acetate=1:1) to provide the title compoundmethyl3-(4-chloro-3-(hydroxymethyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(1.67 g, 3.95 mmol, 81% yield) as a white solid. LC/MS m/z 402.1 (M+H)⁺,1.99 (ret. time).

Methyl3-(4-chloro-3-(chloromethyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To a solution of methyl3-(4-chloro-3-(hydroxymethyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(500 mg, 1.244 mmol) in dichloromethane (DCM) (20 mL) thionyl chloride(296 mg, 2.488 mmol) was added slowly. The reaction mixture was stirredat ambient temperature for 1 h. The solvent was evaporated to obtain thetitle compound methyl3-(4-chloro-3-(chloromethyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(500 mg, 96% yield) which was carried to the next step without furtherpurification. LC/MS m/z 420.1 (M+H)⁺, 1.21 (ret. time).

Methyl3-(4-Chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To a solution of 1-((1H-imidazol-2-yl)methyl)-4-ethylpiperidine (345 mg,1.784 mmol) in N,N-dimethylformamide (DMF) (20 mL)sodium hydride (190mg, 4.76 mmol) was added slowly at ambient temperature under nitrogen.The reaction mixture was stirred for 30 min after which methyl3-(4-chloro-3-(chloromethyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(500 mg, 1.190 mmol) was added. The reaction mixture was stirred atambient temperature for 16 h. The reaction mixture was partitionedbetween ethyl acetate and water. The water layer was extracted withethyl acetate (2×). The combined organic phase was washed with brine anddried over MgSO₄ and concentrated. The crude product was purified bysilica gel chromatography (hexane:ethyl acetate in EtOH=3:1) to obtainthe title compound methyl3-(4-chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(650 mg, 95% yield). LC/MS m/z 577.5 (M+H)+, 1.05 (ret. time).

3-(4-Chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

To a solution of methyl3-(4-chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(65 mg, 0.113 mmol) in methanol (5 mL) LiOH (2M, 0.338 mL, 0.676 mmol)was added. The reaction mixture was heated via microwave at 120° C. for2 h 30 min. The solvent was evaporated and partitioned between ethylacetate and 1 N HCl after which the water layer was adjusted to pH 5,extracted with ethyl acetate (3×). The combined organic phase was driedover MgSO₄ and concentrated to get the title compound (40 mg, 63.1%yield). LC/MS m/z 563.4 (M+H)⁺, 0.98 (ret. time).

Example 237(S)-3-(4-Chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

(S)-Methyl3-(4-chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

Methyl3-(4-chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(650 mg) was separated by Chiral SFC (Column: Chiralpak AD 20×150 mm;Co-solvent: 20% MeOH:IPA (1:1); Flowrate: 50 g/min; Back pressure: 100Bar) to give single enantiomerically pure (S)-methyl3-(4-chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(221 mg, 0.383 mmol, 32.2% yield) (chiral SFC ret. time: 3.62 min) andsingle enantiomerically pure (R)-methyl3-(4-chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(196 mg, 0.340 mmol, 28.5% yield) (chiral SFC ret. time: 5.19 min).

(S)-3-(4-Chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

To a solution of (S)-methyl3-(4-chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(221 mg, 0.383 mmol) in methanol (6 mL) LiOH (2M, 1.915 mL, 3.83 mmol)was added. The reaction was heated via microwave at 120° C. for 2 h. Thesolvent was evaporated and partitioned between ethyl acetate and 1N HCl.The water layer was adjusted to pH 5 and extracted with ethyl acetate(3×). The combined organic layer was dried with MgSO₄ and concentratedto obtain the title compound(S)-3-(4-Chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid (145.1 mg, 67.3% yield). LC/MS m/z 563.4 (M+H)⁺, 0.86 (ret. time).

Example 238(R)-3-(4-Chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

To a solution of (R)-methyl3-(4-chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(196 mg, 0.340 mmol) in methanol (5 mL), LiOH (2M, 1.698 mL, 3.40 mmol)was added. The reaction was heated via microwave at 120° C. for 2 h. Thesolvent was evaporated and partitioned between ethyl acetate and 1 NHCl. The water layer was adjusted to pH 5 and extracted with ethylacetate (3×). The combined organic phase was dried over MgSO₄ andconcentrated to obtain the title compound(R)-3-(4-chloro-3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid (163.6 mg, 71.4% yield). LC/MS m/z 563.3 (M+H)⁺, 0.86 (ret. time).

Example 239(S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid

(S)-Methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To a solution of (S)-methyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate(103 mg, 0.260 mmol) in dichloromethane (DCM) (5 mL), thionyl chloride(0.038 mL, 0.521 mmol) was added. The reaction mixture was stirred atambient temperature for 30 min. The solvent was evaporated to obtain thetitle compound (S)-methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoatewhich was carried to the next step without further purification. LC/MSm/z 414.3 (M+H)⁺, 1.25 (ret. time).

(S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid

To a solution of 1-((1H-imidazol-2-yl)methyl)-4-ethylpiperidine (117 mg,0.604 mmol) in N,N-dimethylformamide (DMF) (5 mL) NaH (19.50 mg, 0.488mmol) was added. After it was stirred for 30 min, (S)-methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(100 mg, 0.242 mmol was added. The reaction mixture was stirred atambient temperature for 2 h. The reaction mixture was partitionedbetween ethyl acetate and water. The water layer was extracted withethyl acetate (2×). The combined organic layer was dried over MgSO₄ andconcentrated to get the crude product which was purified by silica gelchromatography (hexane/ethyl acetate) to obtain (S)-methyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate(120 mg, 87% yield).

To (S)-methyl3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate(120 mg, 0.210 mmol) in methanol (5.00 mL) LiOH (1.208 mL, 2.416 mmol)was added. The reaction was heated via microwave at 120° C. for 2 h. Thesolvent was evaporated and partitioned between ethyl acetate and 1N HCl.The water layer was adjusted to pH 5 and extracted with ethyl acetate(3×). The combined organic phase was dried over MgSO₄ and concentratedto obtain the title compound(S)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid (96 mg, 71.4% yield). LC/MS m/z 557.7 (M+H)⁺, 0.88 (ret. time).

Example 240(3S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid

1-((2-Bromobenzyl)amino)-2-methylbutan-2-ol

To a solution of 2-bromobenzaldehyde (200 mg, 1.081 mmol) in methanol (5mL) 1-amino-2-methylbutan-2-ol (134 mg, 1.297 mmol) and sodium hydroxide(4.32 mg, 0.108 mmol) were added. The reaction mixture was stirred for 8h after which NaBH₄ (40.9 mg, 1.081 mmol) was added and the reactionmixture was stirred at ambient temperature for 16 h. After the solventwas evaporated, the residue was partitioned between ethyl acetate andwater. The water layer was extracted with ethyl acetate (2×). Thecombined organic phase was dried over MgSO₄ and concentrated to obtainthe title compound 1-((2-bromobenzyl)amino)-2-methylbutan-2-ol (275 mg,93% yield) which was carried to the next step without furtherpurification. LC/MS m/z 274.0 (M+H)⁺, 0.62 (ret. time).

2-Ethyl-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of 1-((2-bromobenzyl)amino)-2-methylbutan-2-ol (275 mg,1.010 mmol) in isopropanol (5 mL) cesium carbonate (658 mg, 2.021 mmol)and copper(I) iodide (96 mg, 0.505 mmol) were added. The reactionmixture was stirred while refluxing for 46 h. After it was cooled toambient temperature, the solid was filtered through celite. The filtratewas evaporated and purified by reverse phase preparative HPLC using TFAas a solvent modifier to provide the title compound2-Ethyl-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (88 mg, 45.5%yield). LC/MS m/z 192.6 (M+H)⁺, 0.66 (ret. time).

(3S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid

To a solution of2-ethyl-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (78 mg, 0.406mmol) in N,N-dimethylformamide (DMF) (5 mL) NaH (19.50 mg, 0.488 mmol)was added. After it was stirred for 30 min, (S)-methyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(65 mg, 0.163 mmol) was added. The reaction mixture was stirred atambient temperature for 18 h and partitioned between ethyl acetate andwater. The water layer was extracted with ethyl acetate (2×). Thecombined organic layer was dried over MgSO₄ and concentrated. The crudeproduct was purified by silica gel chromatography (hexane/ethyl acetate)to obtain(3S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate(34 mg, 37.7% yield).

To a solution of(3S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate(34 mg, 0.061 mmol) in methanol (5.00 mL)LiOH (0.813 mL, 1.625 mmol) wasadded. The reaction was heated via microwave at 120° C. for 3 h. Thesolvent was evaporated. The residue was acidified with 1N HCl, then itwas concentrated which was purified by reverse phase preparative HPLC toprovide the title compound(3S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2-ethyl-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid (12.2 mg, 12.88% yield). LC/MS m/z 541.4 (M+H)⁺, 0.95 (ret. time).

Example 241rel-(S)-3-(3-((1-(Cycloheptylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

Example 242rel-(R)-3-(3-((1-(Cycloheptylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

Cycloheptylmethyl 4-methylbenzenesulfonate

The mixture of cycloheptylmethanol (3200 mg, 24.96 mmol) andtriethylamine (5.22 mL, 37.4 mmol) in DCM (50.0 mL) was stirred at 00°C. under nitrogen, TsCl (4996 mg, 26.2 mmol) was added and stirred at 0°C. for 12 h and filtered and concentrated to give the title compoundcycloheptylmethyl 4-methylbenzenesulfonate (3200 mg, 11.33 mmol, 45.4%yield) as an oil. LC/MS m/z 300.2 (M+H₂O)⁺, 2.20 (ret. time).

1-(Cycloheptylmethyl)-1H-1,2,3-triazole

The mixture of cycloheptylmethyl 4-methylbenzenesulfonate (3200 mg,11.33 mmol), 1H-1,2,3-triazole (783 mg, 11.33 mmol) and Cs₂CO₃ (3692 mg,11.33 mmol) in DMF (50.0 mL) was stirred at 00° C. nder nitrogen for 2 hand stirred at 100° C. for 8 h. After it was cooled to ambienttemperature, the solid was filtered and the filtrate was purified byreverse phase preparative HPLC (50% MeOH/H₂O) to provide the titlecompound 1-(cycloheptylmethyl)-1H-1,2,3-triazole (1500 mg, 8.37 mmol,73.8% yield) as a solid. LC/MS m/z 180.1 (M+H)⁺, 1.80 (ret. time).

Methyl3-(3-((1-(cycloheptylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To a solution of 1-(cycloheptylmethyl)-1H-1,2,3-triazole (242 mg, 1.350mmol) in tetrahydrofuran (THF) (10 mL) was added n-butyllithium (0.540mL, 1.350 mmol) at −78° C. under nitrogen. The mixture was stirred at−78° C. for 30 min, then methyl3-(3-(bromomethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(200 mg, 0.450 mmol) in THF (10 mL) was added dropwise and continuallystirred for 2 h at −78° C. The mixture was slowly warmed to ambienttemperature and stirred for an additional 2 h. The reaction mixture wasquenched with saturated aqueous NH₄Cl solution and extracted with ethylacetate (3×). The combined organic layer was washed with brine and driedover anhydrous Na₂SO₄ and concentrated. The residue was purified viasilica gel chromatography (petroleum ether:ethyl acetate=1:3) to obtainthe title compound methyl3-(3-((1-(cycloheptylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(120 mg, 0.219 mmol, 48.6% yield). LC/MS m/z 543.2 (M+H)⁺, 1.88 (ret.time).

3-(3-((1-(Cycloheptylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

To a solution of methyl3-(3-((1-(cycloheptylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(200 mg, 0.369 mmol) in ethylene glycol (4 mL) was added lithiumhydroxide (17.65 mg, 0.737 mmol) in a mixture of water (1 mL) andtetrahydrofuran (THF) (2 mL). The reaction was heated via microwave at125° C. for 2 h after which the organic solvent was removed underreduced pressure and the residue was acidified with 1N HCl to pH 5. Thewhite solid was filtered, collected and dried to provide the titlecompound3-(3-((1-(cycloheptylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid (180 mg, 0.323 mmol, 88% yield). LC/MS m/z 529.2(M+H)⁺, 1.76 (ret.time).

rel-(S)-3-(3-((1-(Cycloheptylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid (isomer 1)rel-(R)-3-(3-((1-(Cycloheptylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid (isomer 2) N35469-69-A2

3-(3-((1-(Cycloheptylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid (480 mg, 0.908 mmol) was purified by Chiral SFC (Column: AS-H(4.6*250 mm, 5 um); Co-solvent MeOH (1% Methanol Ammonia); Flowrate: 50g/min; Back pressure: 100 Bar) to give the title compound(S)-3-(3-((1-(cycloheptylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid (chiral SFC ret. time: 3.45 min) (200 mg, 38.8%) &(R)-3-(3-((1-(cycloheptylmethyl)-1H-1,2,3-triazol-5-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid (chiral SFC ret. time: 4.15 min) (200 mg, 39.6%). LC-MS m/z 529.2(M+H)⁺, 1.76 min (ret. time)

Example 2433-(3-((3H-Spiro[benzo[f][1,4]oxazepine-2,1′-cyclopropan]-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

1-Benzoxy-2-((bis-tert-butoxycarbonyl)amino)methyl-benzene

To a solution of (bis-tert-butoxycarbonyl)amine (8 g, 36.8 mmol) inN,N-dimethylformamide (DMF) (200 mL), Cs₂CO₃ (13.27 g, 40.7 mmol) andsodium iodide (0.509 g, 3.39 mmol) were added at ambient temperature.After the reaction mixture was stirred at ambient temperature for 70min, a solution of 1-(benzyloxy)-2-(chloromethyl)benzene (7.9 g, 33.9mmol) in DMF (50 mL) was added and the resulting mixture was stirred atambient temperature for 20 h. The reaction mixture was quenched withwater and extracted with ethyl acetate (3×). The combined organic layerwas washed with water, brine (2×), dried over Na₂SO₄ and concentrated.The residue was purified by silica gel chromatography (EA:PE=1:2) toobtain the title compound1-benzoxy-2-((bis-tert-butoxycarbonyl)amino)methyl-benzene (11.6 g, 26.7mmol, 79% yield) as a white solid. LC/MS m/z 436.2 (M+Na)⁺, 2.29 min(ret. time)

1-Hydroxy-2-((bis-tert-butoxycarbonyl)amino)methyl-benzene

To a solution of1-benzoxy-2-((bis-tert-butoxycarbonyl)amino)methyl-benzene (11.6 g, 28.1mmol) in a mixture of methanol (100 mL) and tetrahydrofuran (THF) (100mL), palladium/C (10%, 2.99 g, 28.1 mmol) was added. The reactionmixture was stirred at ambient temperature for 6 h under parr shaker at2 atm. The reaction mixture was filtered through celite. The filtratewas concentrated to obtain the title compound1-hydroxy-2-((bis-tert-butoxycarbonyl)amino)methyl-benzene (8.9 g, 26.4mmol, 94% yield) which was carried to the next step without furtherpurification. LC/MS m/z 346.2 (M+Na)+, 2.05 min (ret. time)

Methyl4-bromo-2-(2-(((bis-tert-butoxycarbonyl)amino)methyl)phenoxy)butanoate

To a solution of1-hydroxy-2-((bis-tert-butoxycarbonyl)amino)methyl-benzene (8.9 g, 27.5mmol) in acetonitrile (100 mL) was added methyl 2,4-dibromobutanoate(7.87 g, 30.3 mmol) and Cs₂CO₃ (8.97 g, 27.5 mmol). The reaction mixturewas stirred at 60° C. for 3 h. The reaction mixture was filtered andconcentrated. The crude product was purified by silica gelchromatography (hexane:ethyl acetate=20:1) to obtain the title compoundmethyl4-bromo-2-(2-(((bis-tert-butoxycarbonyl)amino)methyl)phenoxy)butanoate(2.6 g, 4.14 mmol, 15.04% yield) as an oil. LC/MS m/z 524.1 (M+Na)⁺,1.96 min (ret. time)

Methyl1-(2-(((bis-tert-butoxycarbonyl)amino)methyl)phenoxy)cyclopropanecarboxylate

To a solution of methyl4-bromo-2-(2-(((bis-tert-butoxycarbonyl)amino)methyl)phenoxy) butanoate(1.6 g, 3.18 mmol) in tetrahydrofuran (THF) (25 mL), potassiumtert-butoxide (4.78 mL, 4.78 mmol) was added slowly under nitrogen at25° C. The reaction mixture was stirred at 25° C. for 16 h after which10 mL of aqueous NH₄Cl was added and the mixture extracted with ethylacetate (3×), dried over Na₂SO₄ and concentrated to obtain the titlecompound methyl1-(2-(((bis-tert-butoxycarbonyl)amino)methyl)phenoxy)cyclopropanecarboxylate(800 mg, 0.949 mmol, 29.8% yield) which was carried to next step withoutfurther purification. LC/MS m/z 444.0 (M+Na)⁺, 1.60 min (ret. time)

Methyl 1-(2-(aminomethyl)phenoxy)cyclopropanecarboxylate

A solution of methyl1-(2-(((bis-tert-butoxycarbonyl)amino)methyl)phenoxy)cyclopropanecarboxylate (800 mg, 1.898 mmol) in HCl (10 ml, 20.00 mmol) was stirredat 25° C. for 16 h. The reaction mixture was concentrated and purifiedby reverse phase preparative HPLC (solvent: H₂O/MeCN) to provide thetitle compound methyl 1-(2-(aminomethyl)phenoxy)cyclopropanecarboxylate(400 mg, 1.627 mmol, 86% yield) as a white solid. LC/MS m/z 222.2(M+H)⁺, 1.48 min (ret. time)

4,5-Dihydro-3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclopropan]-3-one

A solution of methyl 1-(2-(aminomethyl)phenoxy)cyclopropanecarboxylate(570 mg, 2.58 mmol) and DIPEA (0.450 mL, 2.58 mmol) in 1,4-dioxane (5mL) was heated via microwave at 140° C. for 2 h. The reaction mixturewas concentrated and purified by reverse phase preparative HPLC(solvent: H₂O/MeCN) to provide the title compound4,5-dihydro-3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclopropan]-3-one (150mg, 0.713 mmol, 27.7% yield) as a solid. LC/MS m/z 190.1 (M+H)⁺, 1.42min (ret. time)

4,5-Dihydro-3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclopropane]

To a solution of4,5-dihydro-3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclopropan]-3-one (70mg, 0.370 mmol) in tetrahydrofuran (THF) (50 mL) was added LiAlH₄ (14.04mg, 0.370 mmol) slowly under nitrogen at 20° C. The reaction mixture wasstirred at 20° C. for 4 h after which 10 g of Na₂SO₄ 10H₂O was added.The solid was filtered and concentrated to provide the title compound4,5-dihydro-3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclopropane] (60 mg,0.243 mmol, 65.7% yield) which was carried to next step without furtherpurification. LC/MS m/z 176.1 (M+H)⁺, 1.07 min (ret. time)

Methyl3-(3-((3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclopropan]-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(100 mg, 0.259 mmol) in acetonitrile (5 mL),4,5-dihydro-3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclopropane] (60 mg,0.342 mmol) and K₂CO₃ (95 mg, 0.685 mmol) were added slowly undernitrogen at 25° C. The reaction mixture was stirred at 70° C. for 16 hafter which 20 mL of water was added and the mixture extracted withethyl acetate (3×). The combined organic phase was concentrated. Thecrude product was purified by reverse phase preparative HPLC (solvent:H₂O/MeCN) to provide the title compound ethyl3-(3-((3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclopropan]-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(45 mg, 0.080 mmol, 23.30% yield). LC/MS m/z 525.3 (M+H)⁺, 2.19 min(ret. time)

3-(3-((3H-Spiro[benzo[f][1,4]oxazepine-2,1′-cyclopropan]-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

To a solution of ethyl3-(3-((3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclopropan]-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(45 mg, 0.086 mmol) in tetrahydrofuran (THF) (2 mL) was added a solutionof LiOH (8.22 mg, 0.343 mmol) in water (2.000 mL) slowly under nitrogenat 25° C. The reaction mixture was stirred at 25° C. for 16 h andadjusted to pH 6 with 0.1 N HCl and extracted with ethyl acetate (3×).The combined organic phase was concentrated to provide the titlecompound3-(3-((3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclopropan]-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (30 mg, 0.059 mmol, 69.0% yield). LC/MS m/z 497.2 (M+H)⁺, 1.33 min(ret. time)

Example 2443-(3-((3H-Spiro[benzo[f][1,4]oxazepine-2,1′-cyclobutan]-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

Ethyl 1-(2-formylphenoxy)cyclobutanecarboxylate

To a solution of 2-hydroxybenzaldehyde (5.3 g, 43.4 mmol) inN,N-Dimethylformamide (DMF) (100 mL) was added NaH (2.60 g, 65.1 mmol)slowly under nitrogen at 25° C. The reaction mixture was stirred at 25°C. for 0.5 h after which ethyl 1-bromocyclobutanecarboxylate (8.99 g,43.4 mmol) solution in 5 mL of DMF and KI (0.720 g, 4.34 mmol) wereadded. The reaction mixture was heated at 130° C. for 6 h. After it wascooled to ambient temperature, 100 mL of water was added and the mixtureextracted with ethyl acetate (3×). The combined organic layer wasconcentrated. The crude product was purified by silica gelchromatography (hexane:ethyl acetate=20:1) to provide the title compoundethyl 1-(2-formylphenoxy)cyclobutanecarboxylate (3.4 g, 11.64 mmol,26.8% yield). ¹H NMR (400 MHz, DMSO) b 10.44 (s, 1H), 7.73 (dd, J=7.7,1.7 Hz, 1H), 7.62-7.51 (m, 1H), 7.09 (t, J=7.5 Hz, 1H), 6.55 (d, J=8.4Hz, 1H), 4.16 (q, J=7.1 Hz, 3H), 2.78-2.67 (m, 2H), 1.27-1.15 (m, 4H),1.10 (t, J=7.1 Hz, 3H).

(E)-Ethyl 1-(2-((hydroxyimino)methyl)phenoxy)cyclobutanecarboxylate

To a solution of ethyl 1-(2-formylphenoxy)cyclobutanecarboxylate (3300mg, 13.29 mmol) in a mixture of ethanol (15 mL) and water (5 mL) wasadded hydroxylamine hydrochloride (1847 mg, 26.6 mmol) and ammoniumacetate (3074 mg, 39.9 mmol) slowly under nitrogen at 25° C. Thereaction mixture was stirred at 25° C. for 12 h after which 30 mL ofwater was added and the mixture extracted with ethyl acetate (3×). Thecombined organic phase was concentrated. The crude product was purifiedby silica gel chromatography (hexane:ethyl acetate=10:1) to obtain thetitle compound (Z)-ethyl1-(2-((hydroxyimino)methyl)phenoxy)cyclobutanecarboxylate (1.4 g, 4.79mmol, 36.0% yield). LC/MS m/z 264.1 (M+H)⁺, 1.57 min (ret. time)

Ethyl 1-(2-(aminomethyl)phenoxy)cyclobutanecarboxylate

To a solution of (E)-ethyl1-(2-((hydroxyimino)methyl)phenoxy)cyclobutanecarboxylate (100 mg, 0.380mmol) in acetic acid (5 mL), platinum(IV) oxide (86 mg, 0.380 mmol) wasadded slowly at 25° C. The reaction mixture was hydrogenated at 2 atmfor 6 h and filtered and concentrated to obtain the title compound ethyl1-(2-(aminomethyl)phenoxy)cyclobutanecarboxylate (80 mg, 0.263 mmol,69.3% yield) which was carried to next step without furtherpurification. LC/MS m/z 250.2 (M+H)⁺, 1.56 min (ret. time)

4,5-Dihydro-3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclobutan]-3-one

A solution of ethyl 1-(2-(aminomethyl)phenoxy)cyclobutanecarboxylate (30mg, 0.120 mmol) and DIPEA (0.021 mL, 0.120 mmol) in 1,4-Dioxane (5 mL)was heated via microwave at 140° C. for 2 h and concentrated andpurified by reverse phase preparative HPLC (H₂O/MeCN) to provide thetitle compound4,5-dihydro-3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclobutan]-3-one (5mg, 0.023 mmol, 19.42% yield) as a solid. LC/MS m/z 204.1 (M+H)⁺, 1.39min (ret. time)

4,5-Dihydro-3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclobutane]

To a solution of4,5-dihydro-3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclobutan]-3-one (5mg, 0.025 mmol) in tetrahydrofuran (THF) (5 mL), LiAlH₄ (0.934 mg, 0.025mmol) was added slowly under nitrogen at 20° C. The reaction mixture wasstirred at 20° C. for 4 h. 2 g of Na₂SO₄ 10H₂O was added and filteredand concentrated to obtain the title compound4,5-dihydro-3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclobutane] (3 mg,0.014 mmol, 58.0% yield) which was carried to next step without furtherpurification. LC/MS m/z 190.2 (M+H)⁺, 1.43 min (ret. time)

Ethyl3-(3-((3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclobutan]-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

To a solution of ethyl3-(3-(chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(100 mg, 0.259 mmol) in acetonitrile (5 mL),4,5-dihydro-3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclobutane] (45 mg,0.238 mmol) and K₂CO₃ (65.7 mg, 0.476 mmol) were added slowly undernitrogen at 25° C. The reaction mixture was stirred at 70° C. for 16 hafter which 20 mL of water was added and the mixture extracted withethyl acetate (3×). The combined organic phase was concentrated and thecrude product was purified by reverse phase preparative HPLC (H₂O/MeCN)to provide the title compound ethyl3-(3-((3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclobutan]-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(40 mg, 0.070 mmol, 29.4% yield). LC/MS m/z 539.2 (M+H)⁺, 1.52 min (ret.time)

3-(3-((3H-Spiro[benzo[f][1,4]oxazepine-2,1′-cyclobutan]-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid

To a solution of ethyl3-(3-((3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclobutan]-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(40 mg, 0.074 mmol) in tetrahydrofuran (THF) (2 mL), a solution of LiOH(7.11 mg, 0.297 mmol) in water (2.0 mL) was added slowly under nitrogenat 25° C. The reaction mixture was stirred at 25° C. for 16 h andadjusted to pH=6 with 0.1 N HCl and extracted with ethyl acetate (3×).The combined organic phase was concentrated to obtain the title compound3-(3-((3H-spiro[benzo[f][1,4]oxazepine-2,1′-cyclobutan]-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid (34 mg, 0.063 mmol, 85% yield) as a solid. LC/MS m/z 511.2 (M+H)⁺,1.66 min (ret. time)

Example 2453-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((2-(oxepan-4-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoicacid

2-(Oxepan-4-yl)acetaldehyde

To a solution of 2-(oxepan-4-yl)ethanol (700 mg, 4.85 mmol) indichloromethane (DCM) (10 mL), PCC (2093 mg, 9.71 mmol) was added. Thereaction mixture was stirred at ambient temperature for 12 h. Thereaction mixture was filtered. The filtrate was concentrated to obtainthe title compound 2-(oxepan-4-yl)acetaldehyde (660 mg, 4.18 mmol, 86%yield) which was carried to next step without further purification.LC/MS m/z 143.1 (M+H)⁺, 1.36 min (ret. time)

2-(Oxepan-4-ylmethyl)-1H-imidazole

To a solution of 2-(oxepan-4-yl)acetaldehyde (660 mg, 4.64 mmol) inmethanol (5 mL) and water (5 mL), oxalaldehyde (1347 mg, 9.28 mmol) andammonia hydrate (4555 mg, 32.5 mmol) were added. The reaction mixturewas stirred at 0° C. for 2 h and at ambient temperature for 18 h. Thesolvent was removed and the residue was purified by reverse phasepreparative HPLC (0.05% NH₄HCO₃/H₂O:CH₃CN=5%-95%) to give the titlecompound 2-(oxepan-4-ylmethyl)-1H-imidazole (500 mg, 2.64 mmol, 56.8%yield) as a brown solid. LC/MS m/z 181.2 (M+H)⁺, 1.07 min (ret. time)

Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((2-(oxepan-4-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoate

To a solution of 2-(oxepan-4-ylmethyl)-1H-imidazole (81 mg, 0.450 mmol)in N,N-dimethylformamide (DMF) (5 mL) was added sodium hydride (27.0 mg,1.125 mmol). After it was stirred at 0° C. for 30 min, methyl3-(3-(bromomethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(100 mg, 0.225 mmol) in DMF (2 mL) was added to the mixture slowly andstirred for 1 h at 0° C. Saturated NH₄Cl solution was added and themixture extracted with EtOAc (3×). The combined organic layer was washedwith water (2×), brine (2×), dried over Na₂SO₄ and concentrated toobtain the title compound the methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((2-(oxepan-4-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoate(35 mg, 0.061 mmol, 27.2% yield) as a white solid. LC/MS m/z 544.0(M+H)⁺, 1.87 min (ret. time)

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((2-(oxepan-4-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoicacid

To a solution of methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((2-(oxepan-4-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoate(35 mg, 0.064 mmol) in ethylene glycol (2 mL) was added a solution oflithium hydroxide (3.08 mg, 0.129 mmol) in water (0.5 mL) andtetrahydrofuran (THF) (1 mL). The reaction mixture was heated viamicrowave at 125° C. for 2 h after which the organic solvent wasremoved. The residue was acidified with 1N HCl to pH 6 and the whiteprecipitate was filtered to give the title compound3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((2-(oxepan-4-ylmethyl)-1H-imidazol-1-yl)methyl)phenyl)propanoicacid (25 mg, 0.045 mmol, 69.7% yield). LC/MS m/z 530.3 (M+H)⁺, 1.58 min(ret. time)

Example 2463-(3-((7-Cyclopropyl-2-ethyl-1,4-oxazepan-4-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

3-(4-Methylphenylsulfonamido)propanoic acid

A solution of 3-aminopropanoic acid (9.0 g, 101 mmol) and sodiumhydroxide (8.08 g, 202 mmol) in water (40 mL) was heated to 65° C., then4-methylbenzene-1-sulfonyl chloride (19.26 g, 101 mmol) was added in aportionwise over a period of 0.5 h. Then the reaction mixture wasstirred at 65° C. for another 1 h. The reaction mixture was adjusted toPH=1 with HCl (1N). The solid was filtered to provide the title compound3-(4-methylphenylsulfonamido)propanoic acid (20 g, 82 mmol, 81% yield)which was carried over to next step without further purification. LC/MSm/z 244.0 (M+H)⁺, 1.35 min (ret. time)

N-Methoxy-N-methyl-3-(4-methylphenylsulfonamido)propanamide

A solution of 3-(4-methylphenylsulfonamido)propanoic acid (5.0 g, 20.55mmol) and N,O-dimethylhydroxylamine (2.51 g, 41.1 mmol),1H-benzo[d][1,2,3]triazol-4-ol (2.78 g, 20.55 mmol) andN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (6.38 g,41.1 mmol) and N-ethyl-N-isopropylpropan-2-amine (13.28 g, 103 mmol) indichloromethane (DCM) (100 mL) was stirred at 20° C. for 3 h. Thereaction mixture was concentrated. The residue was dissloved in ethylacetate and washed with 1 N HCl (2×), saturated NaHCO₃ (2×), water,brine (2×), dried over Na₂SO₄ and concentrated to provide the titlecompound N-methoxy-N-methyl-3-(4-methylphenylsulfonamido)propanamide(5.0 g, 17.46 mmol, 85% yield) as a white solid. LC/MS m/z 287.1 (M+H)⁺,1.44 min (ret. time)

N-(3-Cyclopropyl-3-oxopropyl)-4-methylbenzenesulfonamide

To a solution ofN-methoxy-N-methyl-3-(4-methylphenylsulfonamido)propanamide (3.0 g,10.48 mmol) in tetrahydrofuran (THF) (30 mL), cyclopropylmagnesiumbromide (3.04 g, 20.95 mmol) was added at 0° C., and the resultingmixture was stirred at room temperature for 2 h. The mixture wasquenched with saturated NH₄Cl solution and extracted with ethyl acetate(3×). The combined organic layer was washed with water, brine (2×),dried over Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography (ethyl acetate:petroleum ether=1:5) to obtain thetitle compound N-(3-cyclopropyl-3-oxopropyl)-4-methylbenzenesulfonamide(2.15 g, 7.64 mmol, 72.9% yield) as a white solid. LC/MS m/z 268.1(M+H)⁺, 1.87 min (ret. time)

N-(3-Cyclopropyl-3-hydroxypropyl)-4-methylbenzenesulfonamide

To a solution ofN-(3-cyclopropyl-3-oxopropyl)-4-methylbenzenesulfonamide (2.0 g, 7.48mmol) in methanol (20 mL), NaBH₄ (0.425 g, 11.22 mmol) was added inportionwise. The resulting mixture was stirred at room temperature for 2h. The mixture was poured into ice water and then extracted with ethylacetate (2×). The combined organic layer was washed with water, brine(2×), dried over Na₂SO₄ and concentrated to provide the the titlecompound N-(3-cyclopropyl-3-hydroxypropyl)-4-methylbenzenesulfonamide(2.0 g, 7.05 mmol, 94% yield) as a white solid. LC/MS m/z 292.2 (M+H)⁺,1.79 min (ret. time)

N-(3-Cyclopropyl-3-hydroxypropyl)-4-methyl-N-(2-oxobutyl)benzenesulfonamide

To a solution ofN-(3-cyclopropyl-3-hydroxypropyl)-4-methylbenzenesulfonamide (2.0 g,7.43 mmol) in acetone (5 mL), K₂CO₃ (2.052 g, 14.85 mmol) was added,then 1-bromobutan-2-one (1.233 g, 8.17 mmol) was added. The reactionmixture was stirred at room temperature for 16 h. The mixture wasfiltrated. The filtrate was concentrated. The residue was purified bysilica gel chromatography (ethyl acetate:petroleum ether=0 to 30%) toobtain the title compound

N-(3-cyclopropyl-3-hydroxypropyl)-4-methyl-N-(2-oxobutyl)benzenesulfonamide(2.5 g, 7.00 mmol, 94% yield) as a white solid. LC/MS m/z 362.1 (M+Na)⁺,1.78 min (ret. time)

7-Cyclopropyl-2-ethyl-4-tosyl-1,4-oxazepane

To a solution ofN-(3-cyclopropyl-3-hydroxypropyl)-4-methyl-N-(2-oxobutyl)benzenesulfonamide(7.7 g, 22.68 mmol) in dichloromethane (DCM) (100 mL), triethylsilane(2.90 g, 24.95 mmol) and trimethylsilyl trifluoromethanesulfonate (5.55g, 24.95 mmol) were added at −78° C. The reaction mixture was stirred at−78° C. for 10 min. The mixture was quenched by saturated NaHCO₃, thenextracted with CH₂Cl₂ (3×). The combined organic phase was washed withbrine, dried over Na₂SO₄ and concentrated. The residue was purified bysilica gel chromatography (hexane:ethyl acetyate=10:1) to obtain thetitle compound 7-cyclopropyl-2-ethyl-4-tosyl-1,4-oxazepane (6.1 g, 17.92mmol, 79% yield) as a white solid. LC/MS m/z 324.3 (M+H)⁺, 2.21 min(ret. time)

7-Cyclopropyl-2-ethyl-1,4-oxazepane

A mixture of sodium (2.452 g, 107 mmol) and naphthalene (16.64 g, 130mmol) in DME (20 mL) was stirred at room temperature for 2 h. To asolution of 7-cyclopropyl-2-ethyl-4-tosyl-1,4-oxazepane (3.0 g, 9.27mmol) in DME (20 mL) at −78° C., the sodium naphthalenide solution wasadded dropwise until a light green colour presisted. Then the mixturewas quenched with saturated NaHCO₃(20 mL) and DME was removed. Theresidue was diluted with water and was adjust the PH=1 with HCl (1N).Then it was extracted with ethyl acetate (3×). The water layer wasadjust the PH=8 with saturated NaHCO₃ and was extracted with ethylaxcetate (3×). The combined organic phase was washed with brine andconcentrated to provide the title compound7-Cyclopropyl-2-ethyl-1,4-oxazepane (1.5 g, 7.98 mmol, 86%) which wascarried over to next step without further purification. LC/MS m/z 170.1(M+H)⁺, 1.08 min (ret. time)

Tert-Butyl 7-cyclopropyl-2-ethyl-1,4-oxazepane-4-carboxylate

To a solution of 7-cyclopropyl-2-ethyl-1,4-oxazepane (1.5 g, 8.86 mmol)in water (50 mL) was added di-tert-butyl dicarbonate (3.87 g, 17.72mmol) at ambient temperature. The reaction mixture was stirred for 18 h.The reaction mixture was extracted with ethyl acetate (3×). The combinedorganic layer was washed with brine and concentrated. The residue waspurified by silica gel chromatography (ethyl acetate:petroleumether=10:1) to obtain the title compound tert-butyl7-cyclopropyl-2-ethyl-1,4-oxazepane-4-carboxylate (2.17 g, 7.65 mmol,86% yield) as a light yellow oil. LC/MS m/z 214.2 (M-56+H)⁺, 1.91 min(ret. time)

7-Cyclopropyl-2-ethyl-1,4-oxazepane

To a solution of tert-butyl7-cyclopropyl-2-ethyl-1,4-oxazepane-4-carboxylate (2.17 g, 8.06 mmol) indiethyl ether (10 mL) was added hydrogen chloride (0.587 g, 16.11 mmol)at ambient temperature. The reaction mixture was stirred for 18 h. Thereaction mixture was concentrated to obtain the title compound7-cyclopropyl-2-ethyl-1,4-oxazepane, Hydrochloride (1.3 g, 6.00 mmol,74.5% yield) as a yellow oil. LC/MS m/z 170.3 (M+H)⁺, 1.22 min (ret.time)

Methyl3-(3-((7-cyclopropyl-2-ethyl-1,4-oxazepan-4-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

To a solution of methyl3-(3-(bromomethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(70 mg, 0.158 mmol) and 7-cyclopropyl-2-ethyl-1,4-oxazepane (32.0 mg,0.189 mmol) in dichloromethane (DCM) (2 mL) was addedN-ethyl-N-isopropylpropan-2-amine (102 mg, 0.788 mmol). The reactionmixture was stirred at ambient temperature for 2 h and concentrated andthe residue was purified by silica gel chromatography (ethylacetate:petroleum ether=3:1) to give the title compound methyl3-(3-((7-cyclopropyl-2-ethyl-1,4-oxazepan-4-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(60 mg, 0.107 mmol, 67.9% yield) as a light yellow solid. LC/MS m/z533.3 (M+H)⁺, 1.51 min (ret. time)

3-(3-((7-Cyclo propyl-2-ethyl-1,4-oxazepan-4-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid

To a solution of methyl3-(3-((7-cyclopropyl-2-ethyl-1,4-oxazepan-4-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate(60 mg, 0.113 mmol) in ethylene glycol (2 mL) was added a solution oflithium hydroxide (13.49 mg, 0.563 mmol) in water (0.5 mL) andtetrahydrofuran (THF) (1 mL). The reaction was heated via microwave at125° C. for 10 h after which the organic solvent was removed. Theresidue was acidified with 1N HCl to pH 6 and the white precipitate wasfiltered and dried to give the title compound3-(3-((7-Cyclopropyl-2-ethyl-1,4-oxazepan-4-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid ((38 mg, 0.07 mmol, 61.8% yield). LC/MS m/z 519.4 (M+H)⁺, 1.74 min(ret. time)

Example 2473-(3-((2-((4-Ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoicacid

5-(Trimethylsilyl)pent-4-ynal (Intermediate E)

To oxalyl chloride (7.09 ml, 81 mmol) in DCM (100 mL) at −78° C. wasadded dropwise DMSO (9.58 ml, 135 mmol) in DCM (60 mL) and stirred at−78° C. for 5 min and then 5-(trimethylsilyl)pent-4-yn-1-ol (4.22 g, 27mmol) in DCM (35 mL) was added dropwise. Stirring continued for 30 minand then another 30 min at −40 C then triethylamine (30.1 ml, 216 mmol)was added rapidly and and the stirred solution warmed to 0 C and thenpoured into satd aq NaHCO₃. Separate phases and wash DCM with water (2×)and again with satd aq NaHCO₃ and dried (Na₂SO₄) and concentrate to anoil. The crude product was purified on a silica cartridge (80 g) with aCombiflash Companion, eluting at 60 mL/min with a gradient running fromhexanes to 20% EtOAc/hexanes over 25 min. The desired fractions werepooled based on tlc 95% hexane and EtOAc to afford5-(trimethylsilyl)pent-4-ynal (3.15 g, 20.42 mmol, 76% yield).

¹H NMR (400 MHz, CHLOROFORM-d) Q 9.82 (s, 1H), 2.64-2.75 (m, 2H),2.51-2.62 (m, 2H), 0.17 (s, 9H)

1-(3-(((4-Methoxybenzyl)oxy)methyl)-4-methylphenyl)-5-(trimethylsilyl)pent-4-yn-1-ol(Intermediate A)

The reaction was under an inert atmosphere (Ar) in Aldrich anhydrous THF(no stablizer) using glassware dried at 130° C. for >16 h.

4-Bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene (Intermediate5) (3.28 g, 10.22 mmol) was dissolved in anhydrous tetrahydrofuran (THF)(65 mL) and cooled to −65° C. 2M butyllithium in THF (6.39 mL, 12.78mmol) was added and the reaction was stirred at −65° C. to −75° C. for0.5 h. 5-(trimethylsilyl)pent-4-ynal (Intermediate E) (3.15 g, 20.44mmol) in THF (6 mL) was added dropwise and the reaction was stirred at−65° C. to −75° C. for 2 h. The reaction was diluted with water (25 mL)and EtOAc (75 mL). The aqueous layer was extracted with an additionalportion of EtOAc (50 mL) and the combined EtOAc was washed with water(50 mL) and saturated aqueous NaCl (50 mL), dried over Na₂SO₄ andconcentrated. The crude product was dissolved in acetonitrile (15 mL)filtered through a 0.45 μm acrodisc, and purified on a Gilson HPLC(Sunfire Prep C₁₈ OBD 5 mm 30×250 mm preparatory column), under neutralconditions to afford1-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-5-(trimethylsilyl)pent-4-yn-1-ol(3.17 g, 7.99 mmol, 78% yield).

¹H NMR (400 MHz, CHLOROFORM-d) δ 7.26-7.41 (m, 5H), 7.13-7.23 (m, 2H),6.80-6.97 (m, 2H), 4.76-4.89 (m, 1H), 4.47-4.61 (m, 4H), 3.77-3.93 (m,3H), 2.25-2.48 (m, 5H), 1.83-2.10 (m, 3H), 0.10-0.25 (m, 9H).

(5-Bromo-5-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)pent-1-yn-1-yl)trimethylsilane(intermediate B)

To1-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-5-(trimethylsilyl)pent-4-yn-1-ol(Intermediate A) (4.3 g, 10.8 mmol) dissolved in dichloromethane (DCM)(300 mL) was added perbromomethane (4.31 g, 13.00 mmol) and thenpolystyrene-PPh₃ (1.4 mmol/g) (23.21 g, 32.5 mmol) was added. Thereaction slowly spontaneously warmed to 30° C. and was stirred with noexternal cooling or heating for 1.5 h. The reaction was filtered,concentrated and the residue was dissolved in hexane, filtered throughan acrodisc filter and injected onto an ISCO 120 g gold column elutingwith an Combiflash Rf200 at 85 mL/min with a gradient from 0 to 10%EtOAc in hexane to afford(5-bromo-5-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)pent-1-yn-1-yl)trimethylsilane(4.8159 g, 10.48 mmol, 97% yield).

¹H NMR (400 MHz, CHLOROFORM-d) 67.07-7.52 (m, 6H), 6.80-6.99 (m, 2H),5.02-5.21 (m, 1H), 4.41-4.69 (m, 4H), 3.65-3.95 (m, 3H), 2.10-2.66 (m,7H), 0.19 (s, 9H) Icms (1.67 min).

Benzyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-7-(trimethylsilyl)hept-6-ynoate(Intermediate C)

The reaction was under an inert atmosphere (Ar) in aldrich anhydrous THF(no stablizer) using glassware dried at 130° C. for >16 h.

A −70° C. solution of diisopropylamine (12.51 mL, 89 mmol)) intetrahydrofuran (THF) (38 mL) was treated with 1.6 M n-butyllithium inhexanes (33.5 mL, 53.5 mmol) added at a rate that kept the temperature<-60° C. The resulting solution stirred at −70° C. 15 min, warmed to 0°C. over 15 minutes and cooled to −70° C. after which benzyl isobutyrate(9.45 mL, 53.5 mmol) in tetrahydrofuran (THF) (38.0 mL) was addeddropwise while keeping the temperature <-65° C. The reaction was stirredat −70° C. 45 min, warmed to −50° C. for 15 min and then recooled to−70° C.(5-bromo-5-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)pent-1-yn-1-yl)trimethylsilane(Intermediate B) (4.1 g, 8.92 mmol) in tetrahydrofuran (THF) (38.0 mL)was added dropwise to the enolate while keeping the temperature <-60° C.This was immediately followed by the addition of1,3-dimethyltetrahydropyrimidin−2(1H)-one (21.58 mL, 178 mmol) T<-° 60.Stirred 1 h at −70° C. 1 h and then warmed to −45° C. and stirred for 2h. water (25 mL) was added and the mixture warmed to 23° C. Ethylacetate (200 mL) was added and additional water (50 mL) and the phaseswere separated. The aqueous layer was extracted again with EtOAc (75 ml)and the combined extract was washed with water (50 mL) and saturatedaqueous NaCl (50 mL) dried (Na₂SO₄), concentrated and the residue wasinjected as a hexane solution onto an 120 g gold ISCO column elutingwith an Combiflash Rf200, at 85 mL/min with a gradient running fromhexanes to 10% EtOAc/hexanes over 30 min. The desired fractions werepooled and concentrated to afford benzyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-7-(trimethylsilyl)hept-6-ynoate(4.86 g, 8.73 mmol, 98% yield).

¹H NMR (400 MHz, CHLOROFORM-d) δ7.23-7.47 (m, 11H), 7.04-7.17 (m, 2H),6.80-7.02 (m, 3H), 4.91-5.17 (m, 2H), 4.41-4.61 (m, 4H), 3.67-3.94 (m,3H), 2.95-3.13 (m, 1H), 2.19-2.40 (m, 3H), 1.64-2.16 (m, 4H), 1.03-1.24(m, 7H), 0.76-0.94 (m, 1H), 0.15 (s, 9H). LC/MS (ES+) [M+Na+]=579.2(1.74 min)

Benzyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethylhept-6-ynoate(Intermediate D)

Benzyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-7-(trimethylsilyl)hept-6-ynoate(Intermediate C) (2.03 g, 3.65 mmol) dissolved in methanol (18 mL) wascombined with potassium carbonate (2.52 g, 18.23 mmol) and stirred for 2h. The reaction was diluted with water and extracted 3× with DCM. Theorganic layers were dried with MgSO₄, and volatiles were evaporated invacuo to afford benzyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethylhept-6-ynoate(1.67 g, 3.45 mmol, 95%) LC/MS (ES+) [M+Na]+=507.6 (1.54 min)

Benzyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoate

Sodium azide (0.431 g, 6.63 mmol), 1-iodopropane (0.594 mL, 6.10 mmol),copper(I) iodide (0.076 g, 0.398 mmol), and Hunig's base (0.093 mL,0.530 mmol) were added to a solution of benzyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethylhept-6-ynoate(1.284 g, 2.65 mmol) in tert-butanol (6.50 mL) and water (6.5 mL) andheated via microwave at 70° C. for 1 h. This was repeated for a secondequal portion of benzyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethylhept-6-ynoatebenzyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethylhept-6-ynoatefor a total of 2.57 g (5.3 mmol) of the starting acetylene. Bothreactions were cooled and combined, diluted with EtOAc (150 mL) andwater (50 mL). The aqueous layer was extracted again with EtOAc (75 mL)and the combined EtOAc was washed with water (50 mL) and saturatedaqueous NaCl (25 mL), dried (Na₂SO₄) and concentrated. The crude productwas purified on an ISCO 80 g gold column with a Combiflash Rf200 with0-70% EtOAc in hexane at 60 mL/min to afford benzyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoate(2.21 g, 3.88 mmol, 73% yield). LC/MS (ES+) [M+H]+=570.7 (1.43 min).

Benzyl3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoate

Benzyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoate(2.28 g, 4.00 mmol) in acetonitrile (18.0 mL) was combined with cericammonium nitrate (4.39 g, 8.00 mmol) and water (2 mL) and stirred 90min. The reaction was diluted with EtOAc (150 mL) and water (50 mL)shaken and the phases were separated. The aqueous layer was extractedagain with EtOAc (100 mL) and the combined EtOAc was washed with water(50 mL) and saturated aqueous NaCl (50 mL), dried (Na₂SO₄) filtered andthe reaction was concentrated and chromatographed on a 40 g gold columnwith a ISCO Rf200 at 40 ml/min with a gradient from hexane to 100% EtOActo affordbenzyl3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoate(1.63 g, 3.63 mmol, 91% yield). LC/MS (ES+) [M+H]+=450.6 (1.14 min).

Benzyl3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoate(propyl isomer P1) Benzyl3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoate(propyl isomer P2)

In a 25 mL 2 neck flask under Ar,1-((1H-imidazol-2-yl)methyl)-4-ethylpiperidine (156 mg, 0.809 mmol) inN,N-Dimethylformamide (DMF) (4.60 mL) was treated with the portionwiseaddition of 60% sodium hydride in oil (108 mg, 2.70 mmol) and stirredfor 30 min to form solution A.

In a separate vial, benzyl3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoate(303 mg, 0.674 mmol) in dichloromethane (DCM) (4.6 mL) was treated withthionyl chloride (0.098 mL, 1.348 mmol) and the mixture was stirred at23° C. for 30 min. The solvent was removed in vacuo and the residue wasredissolved in N,N-Dimethylformamide (DMF) (4.60 mL) and the resultingsolution was added to solution A described above, and the resultingmixture was stirred for a total of 20 h. The reaction was combined withadditional 1-((1H-imidazol-2-yl)methyl)-4-ethylpiperidine (156 mg, 0.809mmol) and sodium hydride (64.7 mg, 2.70 mmol) and stirred 1 h. Thereaction was diluted with EtOAc (100 mL) and water (50 mL). The aqueouslayer was extracted with a second portion of EtOAc (100 mL) and thecombined EtOAc was washed with water (2×75 mL) and saturated aqueousNaCl, and dried (Na₂SO₄) and concentrated to afford a light green oilwhich was dissolved in DMSO (4 mL) and purified on a Gilson HPLC(Sunfire Prep C₁₈ OBD 5 μm 30×250 mm preparatory column), eluting at 30mL/min with a linear gradient running from 10% CH₃CN/H₂O/0.1% TFA to 95%acetonitrile/H₂O/0.1% TFA over 15 min to afford purified material as amixture of isomers (357 mg).

Separaton of the enantiomers was effected by chiral SFC, Chiralpak AD20×250 mm, 5 u, Co-solvent: 20% MeOH, Total flowrate: 50 g/min, Backpressure: 100 Bar to afford benzyl3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoate(propyl isomer P1) (101 mg, 0.162 mmol, 23.98% yield) LC/MS (ES+)[M+H]+=625.7 (1.15 min). sfc Rf=4.44 min and benzyl3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoate(propyl isomer P2) (82 mg, 0.131 mmol, 19.47% yield) LC/MS (ES+)[M+H]+=625.7 (1.16 min) sfc Rf=5.43 min.

3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoicacid (propyl isomer 2)

Benzyl3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoate(propyl isomer P2) (80 mg, 0.128 mmol) was dissolved in methanol (10 mL)and hydrogenated on an H-cube (flow hydrogenator) with the 20% Pd(OH)₂cartridge at 1 atm for 80 min. The solution was concentrated to afford59.8 mg of a foamy solid. The resulting product was purified by reversephase preparative HPLC using neutral conditions to afford3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoicacid (propyl isomer 2) (32 mg, 0.060 mmol, 47% yield)) as a white solid.LC/MS (ES+) [M+H]+=535.5 (0.90 min).

Example 2483-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoicacid (propyl isomer 1)

Benzyl3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoate(propylisomer P1) (101 mg, 0.162 mmol) was dissolved in methanol (10 mL) andhydrogenated on the H-cube (flow hydrogenator) with the 20% Pd(OH)2cartridge at 1 atm for 50 min. The solvent was removed in vacuo toafford a clear oil which was purified by reverse phase preparative HPLCusing neutral conditions to afford a pure white foamy solid.3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethyl-5-(1-propyl-1H-1,2,3-triazol-4-yl)pentanoicacid (propyl isomer 1) (48 mg, 0.090 mmol, 57%) LC/MS (ES+) [M+H]+=535.5(0.90 min).

Example 2495-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethylpentanoate

Sodium azide (0.553 g, 8.51 mmol), iodoethane (0.684 ml, 8.51 mmol),copper(I) iodide (0.097 g, 0.511 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.119 ml, 0.681 mmol) were added to asolution of benzyl3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethylhept-6-ynoate(1.65 g, 3.40 mmol) (Intermediate D) in tert-butanol (8.51 ml) and water(8.51 ml). This mixture was heated via microwave to 70° C. for 1 hour.The reaction was diluted with water and EtOAc. The aqueous layer wasextracted 3× with EtOAc, and the combined organic layers were dried overMgSO₄ concentrated and the crude oil was purified on a silica cartridge(24 g) with a Combiflash Rf200, eluting at 35 mL/min with a gradientrunning from hexanes to 90% EtOAc/hexanes over 20 min to afford benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(1.57 g, 2.83 mmol, 83% yield) as a yellow oil. LC/MS (ES+) [M+H]+=535.5(0.98 min).

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpentanoate

Ceric ammonium nitrate (3.08 g, 5.61 mmol) was added to a solution ofbenzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(1.56 g, 2.81 mmol) in acetonitrile (12.63 ml) and water (1.404 ml).After 40 min the reaction was diluted with DCM and water. The aqueouslayers were extracted 3× with DCM. The combined organic layers weredried with MgSO₄ and concentrated. The crude oil was purified on asilica cartridge (12 g) with a Combiflash Rf200, eluting at 30 mL/minwith a gradient running from hexanes to EtOAc over 25 min. The desiredfractions were isolated to afford benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpentanoate(1.06 g, 2.44 mmol, 87% yield). LC/MS (ES+) [M+H]+=436.5 (1.09 min).

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(ethyl isomer P1) Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(ethyl isomer P2)

Sodium hydride (55.1 mg, 1.378 mmol) was added to a solution of1-((1H-imidazol-2-yl)methyl)-4-ethylpiperidine (80 mg, 0.413 mmol) inN,N-Dimethylformamide (DMF) (2.296 mL) at 23° C. to afford solution A.

Thionyl chloride (0.050 mL, 0.689 mmol) was added to a solution ofbenzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpentanoate(150 mg, 0.344 mmol) in dichloromethane (DCM) (2.296 mL) at 23° C. After30 min, the volatiles were removed in vacuo. The crude chloride wasdissloved in DMF and added to the solution of1-((1H-imidazol-2-yl)methyl)-4-ethylpiperidine (80 mg, 0.413 mmol) andsodium hydride (55.1 mg, 1.378 mmol) in N,N-Dimethylformamide (DMF)(2.296 mL), solution A, described in the paragraph above. The resultingmixture was stirred at 23° C. for 2 hours. The reaction was quenchedwith NH₄Cl(aqueous layer), and the aqueous layer was extracted 3× withEtOAc. The organic layers were combined, dried with MgSO₄, filtered andconcentrated and the residue was dissolved in MeCN, filtered through a0.45 μm acrodisc, and purified on a Gilson HPLC (YMC C18 5 mm/12 nm50×20 mm preparatory column), eluting at 20 mL/min with a lineargradient running from 5% CH₃CN/H₂O to 65% CH₃CN/H₂O over 10 min. Thedesired fractions were concentrated under a stream of nitrogen at 50°C., giving the mixture of isomers (110 mg, 0.180 mmol). The sample wascombined with a second lot of a mixture of isomers (100 mg) prepared thesame way.

This purified material was purified by chiral SFC, Column: Chiralpak AD20×250 mm, 5 u, Co-solvent: 25% IPA, total flowrate: 50 g/min, Backpressure: 100 Bar to afford Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(ethyl isomer P1) (SFC ret. time 12.19) and Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(ethyl isomer P2) (SFC ret. time 14.12)

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(ethyl isomer P1)

(49 mg, 23%). LC/MS (ES+) [M+H]+=611.4 (1.13 min). Analytical SFC ret.time 12.19.

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(ethyl isomer P2)

(48 mg, 23%) LC/MS (ES+) [M+H]+=611.4 (1.13 min). Analytical SFC ret.time 14.12

5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid (ethyl isomer 2)

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(ethyl isomer P2) (50 mg, 0.082 mmol) was dissolved in MeOH (10 mL), andpassed through an H-cube (flow hydrogenator) at 1 mL/min and 25° C.using a 10% Pd/C cartridge for 1 hour. The methanol was removed in vacuoand the residue was purified by reverse phase preparative HPLC usingneutral conditions to afford5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid (ethyl isomer 2) (20 mg, 0.038 mmol, 46.9% yield). LC/MS (ES+)[M+H]+=521.5 (0.89 min).

Example 2505-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid ethyl isomer 1)

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(ethyl isomer P1) (50 mg, 0.082 mmol) was dissolved in MeOH (10 mL), andpassed through an H-cube (flow hydrogenator) at 1 mL/min and 25 C usinga 10% Pd/C cartridge for 1 hour. The methanol was removed in vacuo andthe residue was purified by reverse phase preparative HPLC using neutralconditions toafford-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-((4-ethylpiperidin-1-yl)methyl)-1H-imidazol-1-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid (ethyl isomer 1) (20 mg, 0.038 mmol, 46.9% yield). LC/MS (ES⁺)[M+H]⁺ 521.5 (0.90 min).

Example 2515-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid

5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpentanoate(enantiomer A1) and

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpentanoate(enantiomer A2) benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpentanoate(998 mg, 2.29 mmol) was submitted to preparative SFC Chiralpak AY 20×250mm, Co-solvent: 25% EtOH, Total flowrate: 50 g/min, Back pressure: 100Bar to afford benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpentanoate(enantiomer A1) 301 mg (30%) g. SFC Rf=1.5 min. LC/MS (ES⁺) [M+H]⁺ 436.5(1.09 min) and then eluting benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpentanoate(enantiomerA2) to afford 303 mg, (30%) SFC Rf=2.42 min. LC/MS (ES⁺) [M+H]⁺=436.5(1.08 min).

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(isomer 1)

To a solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpentanoate(enantiomerA1) (273 mg, 0.627 mmol) in dichloromethane (DCM) (10.0 mL) was addedthionyl chloride (0.183 mL, 2.507 mmol) and the mixture was stirred atambient temperature for 30 min to afford the chlorinated product. Thesolvent was removed and the residue was dissolved in acetonitrile (5.000mL) and the solution was divided into two equal portions and 1/2 of((R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine,hydrochloride (161 mg, 0.752 mmol) (81 mg in each portion) and 1/2 ofHunig'sbase (0.876 mL, 5.01 mmol) (0.438 mL in each portion) each inacetonitrile (5.000 mL) was added to each of the solutions of thechloride product above. Each of the mixtures were heated in a microwavevial at 120° C. for 1 h. The reaction was concentrated and the residuewas shaken with EtOAc (150 mL) and water (50 mL). The aqueous layer wasextracted again with EtOAc (50 mL) and the combined EtOAc was washedwith water (50 mL) and then saturated aqueous NaCl then dried (Na₂SO₄)and concentrated. The crude product was purified on an ISCO gold silicacartridge (12 g) with a Combiflash Rf200, eluting at 30 mL/min with agradient running from hexanes to 100% EtOAc over 25 min. The desiredfractions were pooled and concentrated to afford benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(isomer 1) (283 mg, 0.475 mmol, 76% yield) as a colorless oil. LC/MS(ES⁺) [M+H]⁺ 596.8 (1.08 min).

5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid (isomer 1B)

A solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(isomer 1) (283 mg, 0.475 mmol) in methanol (10 ml) was hydrogenated onthe H-cube (flow hydrogenator) using a 10% Pd—C H cube cartridge andfull H₂ pressure for 45 min. The cartridge was washed with 10 mLmethanol and this was combined with the reaction solution andconcentrated to afford crude product as a white foam. The sample waspurified by neutral Gilson to afford5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid (isomer 1B)(140 mg, 0.277 mmol, 58.3% yield). LC/MS (ES⁺)[M+H]⁺=506.3 (0.86 min).

Example 2525-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid (isomer 2B)

Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(isomer 2)

To a solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpentanoate(enantiomer A2) (0.232 g, 0.533 mmol) in dichloromethane (DCM) (10 mL)was added thionyl chloride (0.078 mL, 1.065 mmol) and stirred at ambienttemperature for 30 min. The solvent was removed and the residue wasdissolved in acetonitrile (5.00 mL). This was divided equally into two20 mL microwave reaction vessels. To each of these solutions was addedone half of a solution of(R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine, hydrochloride(0.114 g, 0.531 mmol) and DIEA (0.372 mL, 2.131 mmol) in acetonitrile(10.00 mL). The reactions were heated via microwave to 120^(□)C. for 1h. Additional (R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine,hydrochloride (0.057 g, 0.266 mmol) and DIEA (0.093 mL, 0.533 mmol) wasdivided equally between each vessel and heated both on microwave at120^(□)C. for 20 min. The reactions were combined and the solvent wasconcentrated. The residue was purified by flash chromatography elutingwith 0-40% (3:1 EtOAc:EtOH)/hexane to provide Benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(isomer 2). (0.233 g, 73% yield) LC/MS m/z=596 (M+H)⁺, 1.11 min(ret.time).

5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid (isomer 2B)

A solution of benzyl5-(1-ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoate(isomer 2) (0.233 g, 0.336 mmol) in methanol (10 mL) was hydrogenated onH-Cube using 10% Pd/C cartridge and full H₂ pressure, for 1.5 h. Thesolvent was concentrated and the residue was purified by reverse phasepreparative HPLC under neutral conditions to provide5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoicacid (isomer 2B). (0.126 g, 74% yield) LC/MS m/z 506 (M+H)+, 0.85 min(ret. time).

Example 2533-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid (100 mg, 0.190 mmol) and cesium carbonate (185 mg, 0.569 mmol) weretaken up in DMF (1.7 mL) at 0° C. Iodomethyl pivalate (138 mg, 0.569mmol) was added. The reaction was stirred at ambient temperature for 18hrs. The reaction was quenched with brine and extracted three times withEtOAc. The organic layers were dried over magnesium sulfate, filtered,and concentrated in vacuo. The crude residue was purified by flashchromatography (gradient 0-5% MeOH/DCM). (S)-(Pivaloyloxy)methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate(69.8 mg, 0.109 mmol, 57.4% yield) after lyophilization.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95 (t, J=7.28 Hz, 3H) 1.07 (s,9H) 1.32 (s, 3H) 1.39 (s, 3H) 1.33-1.44 (m, 1H) 1.59 (d, J=7.28 Hz, 1H)2.24 (s, 3H) 2.76 (s, 3H) 2.79-2.87 (m, 2H) 3.53 (s, 2H) 3.74 (s, 2H)3.80-3.94 (m, 1H) 4.25 (s, 3H) 4.85 (s, 1H) 5.49-5.65 (m, 2H) 6.89 (d,J=5.27 Hz, 1H) 7.03 (s, 3H) 7.27 (d, J=8.53 Hz, 2H) 7.60 (d, J=8.53 Hz,1H) 8.11 (s, 1H) 8.37 (d, J=5.52 Hz, 1H)

LC/MS (ES+): m/z 642.5 (M+H)⁺

Example 254 (S)-((Diphenoxyphosphoryl)oxy)methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

Chloromethyl Diphenyl Phosphate

To a stirring 0° C. solution of diphenyl hydrogen phosphate (10.0 g,40.0 mmol), tetrabutylammonium hydrogensulfate (13.4 g, 160 mmol) inwater (200 mL) was added DCM (100 mL). The resulting mixture was stirredat 0° C. for 10 min and then a solution of chloromethyl sulfochloridate(7.91 g, 48.0 mol) in DCM (100 mL) was added. The resulting solution wasstirred for 3 days at ambient temperature. The organic layer wasseparated and washed with brine, dried over magnesium sulfate, filtered,and concentrated in vacuo. The crude residue was purified by flashchromatography (gradient 0-50% EtOAc/hexanes) to afford chloromethyldiphenyl phosphate (10.37 g, 34.7 mmol, 87% yield) as a colorless oil.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.07 (d, J=16.6 Hz, 2H) 7.21-7.36 (m,6H) 7.41-7.51 (m, 4H) LC/MS (ES+): m/z 299.0 (M+H)⁺

(S)-((Diphenoxyphosphoryl)oxy)methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid (100 mg, 0.190 mmol) and cesium carbonate (185 mg, 0.569 mmol) weretaken up in DMF (1.7 mL) at 0° C. Chloromethyl diphenyl phosphate (170mg, 0.569 mmol) was added. The reaction was stirred at ambienttemperature for 18 hrs, at which point the starting material wasconsumed (>95%). The mono hydrolysis product was the major product. Thereaction was quenched with brine and extracted three times with DCM. Theorganic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo. The crude residue was purified by prep HPLC(20×100 mm Sunfire, 0.1% aq. TFA/CH₃CN). Saturated aqueous NaHCO₃ wasadded to the product fractions to free base the product. The product wasextracted with DCM (3×) from this aqueous layer. The combined organiclayers were dried over magnesium sulfate, filtered, concentrated invacuo, and lyophilized to provide (S)-((diphenoxyphosphoryl)oxy)methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoateat 77% purity. Product is a mixture of diastereomers at phosphorus,diastereomeric peaks are denoted in pairs, where applicable, in the NMRcharacterization.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.94 (t, J=7.53 Hz, 3H) 1.01/1.13(s, 3H) 1.08/1.18 (s, 3H) 1.27-1.45 (m, 1H) 1.58-1.62 (m, 1H) 1.95(br.s. 1H) 2.18/2.23 (s, 3H) 2.65/2.73 (s, 3H) 2.79-2.86 (m, 2H)3.45/3.53 (s, 2H) 3.73/3.86 (s, 2H) 3.80-3.94 (m, 1H) 4.10/4.22 (s, 3H)4.66/4.76 (s, 1H) 5.17-5.34 (m, 2H) 6.75-7.07 (m, 9H) 7.15/7.24 (d,J=7.78 and 8.78 Hz, respectively, 1H) 7.42/7.57 (d, J=both 8.53 Hz, 1H)8.04/8.11 (s, 1H) 8.22/8.37 (d, J=3.26 and 5.27 Hz, respectively, 1H)

LC/MS (ES+): m/z 714.2 (M+H)⁺

Example 2553-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

Chloromethyl Phenyl Methylphosphate

Methylphosphonic dichloride (15.3 g, 115 mmol) was weighed into a dry500 mL round bottom flask. Phenol (21.7 g, 230 mmol) and DCM (209 mL)were added. The resulting mixture was stirred as it was cooled to 0° C.Triethylamine (64.2 mL, 460 mmol) was added dropwise over 1 hr forming acolorless precipitate. The mixture was allowed to warm to ambienttemperature and stirred for an additional 2 hrs. The mixture wascarefully poured into ice water (100 mL) The organics were extractedwith DCM (2×), dried over magnesium sulfate, filtered, and concentratedin vacuo. The crude product was purified by flash chromatography(gradient 0-50% EtOAc/hexanes) to afford diphenyl methylphosphonate(24.6 g, 99.0 mmol, 86% yield) as a viscous oil. LC/MS (ES+): m/z 249.0(M+H)⁺

Diphenyl methylphosphonate (24.6 g, 99.0 mmol) was diluted in water (150mL). Aqueous sodium hydroxide (2N, 74.4 mL, 149 mmol) was added. Theresulting mixture was stirred at reflux for 30 minutes until the organicphase became miscible with the aqueous solvent. The mixture was thencooled to 0° C. and concentrated HCl (16.53 mL, 99.0 mol) was carefullyadded to neutralize the solution to approximately pH=7. The aqueousphase was washed with DCM to remove the phenol byproduct. The aqueousphase was brought to pH=1 using concentrated HCl. The aqueous phase wasextracted with DCM (3×) and the combined organic layers were washed withbrine and then dried over magnesium sulfate, filtered, and concentratedto give phenyl hydrogen methylphosphonate (7.17 g, 35.4 mmol, 35.7%yield) as an orange oil, which was carried on to the next step withoutfurther purification. LC/MS (ES+): m/z 172.9 (M+H)⁺

To a stirring 0° C. solution of phenyl hydrogen methylphosphonate (7.17g, 41.7 mmol), tetrabutylammonium hydrogensulfate (1.41 g, 4.17 mmol)and NaHCO₃ (14.0 g, 167 mmol) in water (208 mL) was added DCM (100 mL)The resulting mixture was stirred at 0° C. for 10 min and then asolution of chloromethyl sulfochloridate (8.25 g, 50.0 mmol) in DCM (100mL) was added and the reaction was stirred for 18 hrs at ambienttemperature. The reaction was recharged with chloromethylsulfochloridate (8.25 g, 50.0 mmol). After 2 hrs, the reaction was atpH=1, so sodium carbonate (8.83 g, 83 mmol) was added. No furtherprogression was observed so chloromethyl sulfochloridate (8.25 g, 50.0mmol) was added and the mixture was stirred for 18 hr at ambienttemperature. A final addition of sodium carbonate (8.83 g, 83 mmol)followed by chloromethyl sulfochloridate (8.25 g, 50.0 mmol) wasperformed and the mixture was stirred at ambient temperature for 1 hr.The organic layer was separated and concentrated in vacuo. The cruderesidue was purified by flash chromatography (gradient 0-50%EtOAc/hexanes) to afford chloromethyl phenyl methylphosphonate (3.36 g,15.23 mmol, 36.6% yield) as a yellow oil. Product is a mixture ofdiastereomers at phosphorus, diastereomeric peaks are denoted in pairs,where applicable, in the NMR characterization.

¹H NMR (400 MHz, DMSO-d₆) b ppm 1.77/1.81 (s, 3H) 5.90/5.94 (m, 2H)7.17-7.30 (m, 3H) 7.37-7.46 (m, 2H)

LC/MS (ES+): m/z 220.9 (M+H)⁺

3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid (100 mg, 0.190 mmol) and cesium carbonate (185 mg, 0.569 mmol) weretaken up in DMF (1.7 mL) at 0° C. Chloromethyl phenyl methylphosphonate(125 mg, 0.569 mmol) was added. The reaction was stirred at ambienttemperature overnight, at which point the starting material was consumedby LC/MS analysis. The reaction was quenched with brine and extractedwith DCM (3×). The combined organic layers were dried over magnesiumsulfate, filtered, and concentrated in vacuo. The crude residue waspurified by reverse phase acidic prep HPLC to separate out the byproductcleanly (Sunfire, TFA modifier). The purified fractions were washed withsaturated NaHCO₃ to remove the TFA salt and the product was extractedwith DCM. The combined organic layers were dried over magnesium sulfate,filtered, and concentrated to provide(3S)-((methyl(phenoxy)phosphoryl)oxy)methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate(20.3 mg, 0.029 mmol, 15.05% yield) after lyophilization.

¹H NMR (400 MHz, CHLOROFORM-d) b ppm 0.96/0.97 (t, J=7.30 Hz, 3H)1.31/1.34 (s, 3H) 1.39/1.40 (s, 3H), 1.36-1.42 (m, 1H), 1.48/1.52 (d,J=6.15 Hz, 3H) 1.56-1.67 (m, 1H) 2.26 (s, 2×3 H, overlapping) 2.77/2.78(s, 3H) 2.81-2.91 (m, 2H, overlapping) 3.54 (s, 2×2 H, overlapping) 3.75(s, 2×2 H, overlapping) 3.83-3.96 (m, 1H, overlapping) 4.24/4.25 (s, 3H)4.84/4.87 (s, 2H) 5.39-5.62 (m, 2H, overlapping) 6.91 (d, J=5.27 Hz, 1H)6.99-7.10 (m, 3H) 7.11-7.23 (m, 3H) 7.26 (m, 1H) 7.30-7.38 (m, 2H)7.57/7.63 (d, J=8.78 Hz, 1H) 8.12 (d, J=3.01 Hz, 1H) 8.39 (d, J=5.02 Hz,1H) LC/MS (ES+): m/z 712.2 (M+H)⁺

Example 2563-((S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoyl)thiazolidin-2-one,Trifluoroacetic acid salt

Oxalyl chloride (0.166 mL, 1.895 mmol) was added to a solution of(S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid (100 mg, 0.190 mmol) in DCM (2 mL). Catalytic DMF (2 drops) wasadded. Additional oxalyl chloride (0.166 mL, 1.895 mmol) was added inorder to complete the formation of the intermediate acid chloride, atwhich point the reaction was concentrated in vacuo to provide the acidchloride hydrochloride salt as a white foam. This crude material wasredissolved in DCM (2 mL). DIPEA (0.331 mL, 1.895 mmol) followed bythiazolidin-2-one (98 mg, 0.948 mmol) was added. The reaction wasstirred at ambient temperature for 15 minutes, during which time thereaction turned a dark brown color. The reaction was quenched withsaturated aqueous NaHCO₃ and extracted with DCM (3×). The organic layerswere washed with brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The crude residue was first purified by flashchromatography (100% DCM) and then further purified by reverse phaseacidic prep HPLC (Sunfire, TFA modifier) to provide the trifluoroaceticacid salt of3-((S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoyl)thiazolidin-2-one(61.6 mg, 0.080 mmol, 42.0% yield) as a white solid afterlyophilization.

¹H NMR (400 MHz, CHLOROFORM-d) b ppm 1.00 (t, J=7.40 Hz, 3H) 1.43 (s,3H) 1.53 (s, 3H) 1.55-1.67 (m, 1H) 1.67-1.80 (m, 1H) 2.23 (s, 3H)2.53-2.67 (m, 1H) 2.69-2.78 (m, 1H) 2.80 (s, 3H) 3.00-3.13 (m, 2H) 3.77(s, 2H) 3.79-3.91 (m, 4H) 4.26 (s, 3H) 4.23 (d, J=15.31 Hz, 2H)4.44-4.51 (m, 1H) 5.65 (s, 1H) 7.03-7.18 (m, 3H) 7.23 (d, J=6.02 Hz, 1H)7.32 (d, J=8.78 Hz, 1H) 7.53 (d, J=8.53 Hz, 1H) 8.40 (s, 1H) 8.53 (d,J=6.27 Hz, 1H)

¹⁹F NMR (376 MHz, CHLOROFORM-d) Q ppm-75.72

LC/MS (ES+): m/z 613.4 (M+H)⁺

Example 2573-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid (86 mg, 0.163 mmol) was taken up in DCM (2 mL). Oxalyl chloride(0.16 mL, 1.828 mmol) followed by catalytic DMF (1 drop) was added andthe reaction stirred for 90 minutes. To this reaction mixture was addedexcess ethanol (2 mL). The reaction was then diluted with saturatedaqueous NaHCO₃ and extracted with DCM (3×). The combined organic layerswere washed with brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The crude residue was purified by reverse phaseacidic prep HPLC (Sunfire, TFA modifier). The purified product fractionswere free based with saturated aqueous NaHCO₃ to remove the TFA salt andthe product was extracted from the aqueous layer with DCM. The combinedorganic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo to provide (S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate(13.4 mg, 0.024 mmol, 14.8% yield) as a white solid after lyophlization.

¹H NMR (400 MHz, CHLOROFORM-d) b ppm 0.95 (q, J=7.28 Hz, 6H) 1.31 (s,3H) 1.38 (s, 3H) 1.55-1.65 (m, 1H) 2.25 (s, 3H) 2.78 (s, 3H) 2.79-2.90(m, 2H) 3.54 (s, 2H) 3.76 (s, 2H) 3.83-4.00 (m, 3H) 4.25 (s, 3H) 4.83(s, 1H) 6.90 (d, J=5.27 Hz, 1H) 7.00-7.09 (m, 3H) 7.27 (d, J=8.60 Hz,1H) 7.64 (d, J=8.78 Hz, 1H) 8.16 (s, 1H) 8.39 (d, J=5.02 Hz, 1H)

LC/MS (ES+): m/z 556.2 (M+H)⁺

Example 258 (S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2.3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propionate

To a solution of (S)-ethyl3-(3-chloromethyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate(119 mg, 0.308 mmol) and DIEA (0.164 mL, 0.939 mmol) in acetonitrile(2.0 mL) was added(R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine, hydrochloride(101 mg, 0.469 mmol) and the reaction mixture was stirred at 60° C. for4 hrs. The reaction mixture was cooled, the solvent evaporated, and thecrude residue partitioned between DCM and H₂O, the layers separated andthe organic phase dried over Na₂SO₄, filtered and the solvent evaporatedunder reduced pressure. The crude residue was purified by flash columnchromatography (SiO₂; 24 g) eluting with a 100% hexanes to 60%EtOAc-hexanes gradient over 15 min to afford 101.3 mg (61%) of titlecompound as a white foam. LC-MS m/z 528.4.

(S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2.3-dihydropyrido[2,3-t][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propionicacid

To a solution of (S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2.3-dihydropyrido[2,3-ft][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propionate(101 mg, 0.191 mmol) in ethanol (2.0 mL) was added 2N NaOH (0.782 mL,1.56 mmol) and the reaction mixture was stirred at 60° C. for 18 hrs.The reaction mixture was cooled and the solvent evaporated using aDry-column nitrogen blowdown unit at 50° C. The crude residue waspartitioned between EtOAc and H₂O, the pH of the aqueous adjusted to pH6 with 1N HCl, the layers separated, the aqueous phase extracted withEtOAc (2×), the organics combined, washed with H₂O, brine, dried overNa₂SO₄, filtered and the solvent evaporated under reduced pressure. Thecrude residue was purified by flash column chromatography (SiO₂; 12 g)eluting with a 100% CH₂Cl₂ to 10% MeOH—CH₂Cl₂ gradient over 15 min toafford 73.8 mg (77%) of title compound as a white solid. LC-MS m/z503.2. ¹H NMR (400 MHz, DMSO-d₆) b: 0.93 (t, J=7.4 Hz, 3H), 1.31 (ddd,J=13.9, 7.3, 4.1 Hz, 1H), 1.42-1.59 (m, 1H), 2.19 (s, 3H), 2.64-2.92 (m,5H), 3.04 (d, J=7.8 Hz, 2H), 3.51 (s, 2H), 3.73-3.98 (m, 3H), 4.24 (s,3H), 4.78 (t, J=7.8 Hz, 1H), 7.02-7.07 (m, 1H), 7.08-7.14 (m, 2H), 7.27(dd, J=8.0, 4.5 Hz, 1H), 7.39 (dd, J=8.0, 1.3 Hz, 1H), 7.45-7.57 (m,2H), 8.18 (dd, J=4.6, 1.4 Hz, 1H), 12.14 (br. s., 1H).

The compounds in Table 25 were prepared by a method similar to the onedescribed for the preparation of (S)-ethyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2.3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propionate.As is appreciated by those skilled in the art, these analogous examplesmay involve variations in general reaction conditions.

TABLE 25 LCMS Retention Ex # Structure Name [m + H]⁺ Time (min) 259

(S)-3-(1,4-dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3- dihydropyrido[4,3- f][1,4]oxazepin-4(5H)-yl)methyl)-4- methylphenyl)propanoic acid 503.2 1.32 260

(S)-3-(1,4-dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3- dihydropyrido[4,3- f][1,4]oxazepin-4(5H)-yl)methyl)-4- fluorophenyl)propanoic acid 504.2 1.51 261

rel-(R)-3-(1,4-dimethyl- 1H-benzo[d]- [1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3- dihydropyrido[2,3- f][1,4]oxazepin-4(5H)-yl)methyl)-4- fluorophenyl)-propanoic acid (isomer 1) 504.3 0.69 262

rel-(R)-3-(4-chloro-3- ((2,2-dimethyl-2,3- dihydropyrido[2,3-f][1,4]oxazepin-4(5H)- yl)methyl)phenyl)-3-(1,4- dimethyl-1H-benzo[d][1,2,3]triazol-5- yl)propanoic acid (isomer 1) 520.3 0.8 263

(S)-3-(4-chloro-3-(((R)-2- ethyl-2,3- dihydropyrido[2,3-f][1,4]oxazepin-4(5H)- yl)methyl)phenyl)-3-(1,4- dimethyl-1H-benzo[d][1,2,3]triazol-5- yl)propanoic acid 520.2 1.62 264

(S)-3-(1,4-dimethyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl- 2,3-dihydropyrido[4,3- f][1,4]oxazepin-4(5H)-yl)methyl)-4- methylphenyl)propanoic acid 500.2 1.55

What is claimed is:
 1. A compound of Formula (I)

wherein, B is benzotriazolyl, phenyl or triazolopyridinyl, each of whichis unsubstituted or substituted by 1, 2, or 3 substituents independentlyselected from —C₁₋₃alkyl, —O—C₁₋₃alkyl, CN, —(CH₂)₂—O—(CH₂)₂—OR₄ andhalo; D is —C(O)OH, —C(O)NHSO₂CH₃, —SO₂NHC(O)CH₃,5-(trifluoromethyl)-4H-1,2,4-triazol-2-yl, or tetrazolyl; R₁ isindependently hydrogen, C₁₋₃alkyl, F, or the two R, groups together withthe carbon to which they are attached form a cyclopropyl group; R₂ ishydrogen, methyl, CF₃, or halo; R₄ is hydrogen or —C₁₋₃alkyl; Linker is—CH₂—, —CH₂—N(-cyclopropyl)-CH₂—, —CH₂—N(CH₃)—CH₂— or —N—(CH₃)—CH₂—; Ais tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl,tetrahydrobenzazepinyl, phenyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, tetrahydropyrrolopyrazinyl, imidazopyridinyl, pyridyl,benzimidazolyl, tetrahydrobenzodiazepinyl, piperidopyrimidinyl,dioxidotetrahydrothiophenyl, tetrahydroimidazodiazepinyl, pyrrolidinyl,oxazepane or morpholinyl; each of which is unsubstituted or substitutedby 1, 2, or 3 substituents independently selected from —C₁₋₃alkyl,C₃₋₆spirocycloalkyl, halo, CN, —O—C₁₋₃alkyl, —CH₂—O—CH₃, and OH; and thepiperidinyl is unsubstituted or additionally substituted by one or twosubstituents independently selected from pyrazolyl, —CH₂pyrazolyl, andoxadiazolyl, each of which is unsubstituted or further substituted byone or two —C₁₋₃alkyl, or, when A is piperidinyl, it is unsubstituted orsubstituted by —SO₂R, wherein R is —C₁₋₃alkyl, phenyl or C₃₋₇cycloalkyl;and the oxazepane is unsubstituted or substituted by 1 or 2 substituentsindependently selected from —C₁₋₃alkyl and —C₃₋₇cycloalkyl; and themorpholinyl is unsubstituted or substituted by a phenyl which itself isunsubstituted or substituted by one or two substituents independentlyselected from C₁₋₃ alkyl and —O—C₁₋₃alkyl; and the pyrrolidinyl isunsubstituted or substituted by a triazolyl group which itself isunsubstituted or substituted by —C₁₋₃alkyl; and the imidazolyl,triazolyl, pyrazolyl, and tetrazolyl groups are each unsubstituted orsubstituted by one or two substituents independently selected from—CH₂—C₄₋₇cycloalkyl, —CH₂—C₅₋₇heterocycloalkyl, —CH₂-azabicycloheptanyl,—CH₂-oxepane and —CH₂— azabicyclohexanyl, each of which, including the—CH₂—, is unsubstituted or further substituted by 1 or 2 substituentsindependently selected from —C₁₋₃ alkyl and F; and X is independently CHor N; or a pharmaceutically acceptable salt thereof.
 2. The compound ofclaim 1, wherein, B is benzotriazolyl which is unsubstituted orsubstituted by 1, 2, or 3 substituents independently selected from—C₁₋₃alkyl and halo; D is —C(O)OH, —C(O)NHSO₂CH₃, or tetrazolyl; R₁ isindependently hydrogen or methyl or the two R, groups together with thecarbon to which they are attached form a cyclopropyl group; R₂ is methylor halo; Linker is —CH₂—; A is tetrahydrobenzoxazepinyl,tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, ortetrahydrobenzodiazepinyl; each of which is unsubstituted or substitutedby 1, 2, or 3 substituents independently selected from —C₁₋₃ alkyl,halo, CN, and —OC₁₋₃alkyl; and the piperidinyl is unsubstituted oradditionally substituted by pyrazolyl or oxadiazolyl each of which isunsubstituted or further substituted by —C₁₋₃alkyl or, when A ispiperidinyl, it is unsubstituted or substituted by —SO₂R, wherein R is—C₁₋₃alkyl, phenyl or C₃₋₇cycloalkyl; and each of the imidazolyl,triazolyl, pyrazolyl, and tetrazolyl groups is independentlyunsubstituted or additionally substituted by one or two substituentsindependently selected from —CH₂—C₄₋₇cycloalkyl, —CH₂-oxepane and—CH₂—C₅₋₇; and X is independently CH or N; or a pharmaceuticallyacceptable salt thereof.
 3. The compound of claim 1, wherein, B isbenzotriazolyl which is unsubstituted or substituted by 1, 2, or 3substituents independently selected from —C₁₋₃alkyl and halo; D is—C(O)OH; R₁ is independently hydrogen or methyl or the two R₁ groupstogether with the carbon to which they are attached form a cyclopropylgroup; R₂ is methyl or halo; Linker is —CH₂—; A istetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl,tetrahydrobenzazepinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, ortetrahydrobenzodiazepinyl; each of which is unsubstituted or substitutedby 1, 2, or 3 substituents independently selected from —C₁₋₃ alkyl,halo, CN, and —OC₁₋₃alkyl; and the piperidinyl is unsubstituted oradditionally substituted by pyrazolyl or oxadiazolyl each of which isunsubstituted or further substituted by —C₁₋₃alkyl or, when A ispiperidinyl, it is unsubstituted or substituted by —SO₂R, wherein R is—C₁₋₃alkyl, phenyl or C₃₋₇cycloalkyl; and each of the imidazolyl,triazolyl, pyrazolyl, and tetrazolyl groups is unsubstituted oradditionally substituted by one or two substituents independentlyselected from —CH₂—C₄₋₇cycloalkyl, —CH₂-oxepane and —CH₂—C₅₋₇; and X isCH; or a pharmaceutically acceptable salt thereof.
 4. The compound ofclaim 1, wherein, B is benzotriazolyl which is unsubstituted orsubstituted by 1, 2, or 3 substituents independently selected from—C₁₋₃alkyl and halo; D is —C(O)OH; R₁ is independently hydrogen orC₁₋₃alkyl; R₂ is methyl or chloro; Linker is —CH₂—; A istetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl,tetrahydrobenzazepinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, ortetrahydrobenzodiazepinyl; each of which is unsubstituted or substitutedby 1, 2, or 3 substituents independently selected from —C₁₋₃ alkyl,halo, CN, and —OC₁₋₃alkyl; and the piperidinyl is unsubstituted oradditionally substituted by pyrazolyl or oxadiazolyl each of which isunsubstituted or further substituted by —C₁₋₃alkyl or, when A ispiperidinyl, it unsubstituted or substituted by —SO₂R, wherein R is—C₁₋₃alkyl, phenyl or C₃₋₇cycloalkyl; and the imidazolyl, triazolyl,pyrazolyl, and tetrazolyl groups are each unsubstituted or additionallysubstituted by 1 or 2 substituents independently selected from—CH₂—C₄₋₇cycloalkyl, —CH₂-oxepane and —CH₂—C₅₋₇; and X is CH; or apharmaceutically acceptable salt thereof.
 5. A compound which is:(S)-Methyl3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid;3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid;(R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid;(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid;(2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid;(2R,3S)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid;(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid;(S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2.3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propionicacid;rel-(R)-3-(1,4-dimethyl-1H-benzo[d]-[1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-fluorophenyl)-propanoicacid;rel-(R)-3-(4-chloro-3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid;(S)-3-(4-chloro-3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoicacid;3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid;(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid;(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9-fluoro-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid;(S)-3-(3-(((R)-8-Chloro-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid;(R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid;3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid;(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid;3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid;3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,8-trimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoicacid;(S)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid;(R)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid;3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoicacid;(2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid;(2S,3R)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid;(2S,3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid;(2R,3S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid;(R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid;(2R,3S)-3-(7-Chloro-1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid;3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoicacid;3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoicacid;(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-6-fluoro-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid;3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid;3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid;3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,8-trimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)pronoicacid;3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid;3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid;(2R,3S)-3-(4-Chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoicacid;(2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoicacid;(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-N-(methylsulfonyl)propenamide;(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoicacid;(S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid;(S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-fluorophenyl)propanoicacid; or(S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid, or a pharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition comprising the compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and one or more of pharmaceutically acceptableexcipients.
 7. A method of treating respiratory and non-respiratorydisorders, including COPD, asthma, fibrosis, chronic asthma, acuteasthma, lung disease secondary to environmental exposures, acute lunginfection, chronic lung infection, al antitrypsin disease, cysticfibrosis, autoimmune diseases, diabetic nephropathy, chronic kidneydisease, sepsis-induced acute kidney injury, acute kidney injury (AKI),kidney disease or malfunction seen during kidney transplantation,Pulmonary Arterial Hypertension, atherosclerosis, hypertension, heartfailure, acute coronary syndrome, myocardial infarction, myocardialrepair, cardiac remodeling, cardiac arrhythmias, heart failure withpreserved ejection fraction, heart failure with reduced ejectionfraction, diabetic cardiomyopathy, Parkinson's disease (PD), Alzheimer'sdisease (AD), Friedreich's Ataxia (FA), amyotrophic lateral sclerosis(ALS), multiple sclerosis (MS), inflammatory bowel disease, coloncancer, neovascular (dry) AMD and neovascular (wet) AMD, eye injury,Fuchs Endothelial Corneal Dystrophy (FECD), uveitis or otherinflammatory eye conditions, Non-alcoholic Steatohepatitis (NASH),toxin-induced liver disease (e.g., acetaminophen-induced hepaticdisease), viral hepatitis, cirrhosis, psoriasis, dermatitis/topicaleffects of radiation, immunosuppression due to radiation exposure,Preeclampsia, and high altitude sickness, which comprises administeringto a human in need thereof, a therapeutically effective amount of thecompound, or a pharmaceutically acceptable salt thereof, of claim
 1. 8.The method of claim 7 wherein the compound, or a pharmaceuticallyacceptable salt thereof, is administered orally.
 9. The method of claim7 wherein the compound, or a pharmaceutically acceptable salt thereof,is administered intravenously.
 10. The method of claim 7 wherein thedisease is heart failure.
 11. A compound which is3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoicacid

or a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising the compound of claim 11, or a pharmaceuticallyacceptable salt thereof, and one or more of pharmaceutically acceptableexcipients.
 13. A method of treating respiratory and non-respiratorydisorders, including COPD, asthma, fibrosis, chronic asthma, acuteasthma, lung disease secondary to environmental exposures, acute lunginfection, chronic lung infection, al antitrypsin disease, cysticfibrosis, autoimmune diseases, diabetic nephropathy, chronic kidneydisease, sepsis-induced acute kidney injury, acute kidney injury (AKI),kidney disease or malfunction seen during kidney transplantation,Pulmonary Arterial Hypertension, atherosclerosis, hypertension, heartfailure, acute coronary syndrome, myocardial infarction, myocardialrepair, cardiac remodeling, cardiac arrhythmias, heart failure withpreserved ejection fraction, heart failure with reduced ejectionfraction, diabetic cardiomyopathy, Parkinson's disease (PD), Alzheimer'sdisease (AD), Friedreich's Ataxia (FA), amyotrophic lateral sclerosis(ALS), multiple sclerosis (MS), inflammatory bowel disease, coloncancer, neovascular (dry) AMD and neovascular (wet) AMD, eye injury,Fuchs Endothelial Corneal Dystrophy (FECD), uveitis or otherinflammatory eye conditions, Non-alcoholic Steatohepatitis (NASH),toxin-induced liver disease (e.g., acetaminophen-induced hepaticdisease), viral hepatitis, cirrhosis, psoriasis, dermatitis/topicaleffects of radiation, immunosuppression due to radiation exposure,Preeclampsia, and high altitude sickness, which comprises administeringto a human in need thereof, a therapeutically effective amount of thecompound, or a pharmaceutically acceptable salt thereof, of claim 11.14. The method of claim 13 wherein the compound, or a pharmaceuticallyacceptable salt thereof, is administered orally.
 15. The method of claim13 wherein the compound, or a pharmaceutically acceptable salt thereof,is administered intravenously.
 16. The method of claim 13 wherein thedisease is heart failure.
 17. A method of treating heart failure whichcomprises administering to a human in need thereof, a therapeuticallyeffective amount of the compound, or a pharmaceutically acceptable saltthereof, of claim
 11. 18. The method of claim 17 wherein the compound,or a pharmaceutically acceptable salt thereof, is administered orally.19. The method of claim 17 wherein the compound, or a pharmaceuticallyacceptable salt thereof, is administered intravenously.